NOVEL COMPOUNDS

Abstract

The present invention relates to compounds of formula (I) wherein Q is selected from O or S; R.sup.1 is a saturated or unsaturated, optionally substituted hydrocarbyl group optionally including one or more heteroatoms N, O or S; R.sup.2 is a cyclic group substituted at the a and a positions, wherein the substituent at the -position is a monovalent heterocyclic group or a monovalent aromatic group, wherein the heterocyclic or aromatic group may optionally be substituted, and wherein the cyclic group may optionally be further substituted; R.sup.3 and R.sup.4 are each independently hydrogen, halogen, OH, NH.sub.2, CN, R.sup.5, OR.sup.5, NHR.sup.5 or N(R.sup.5).sub.2; or R.sup.3 and R.sub.4 together with the carbon atom to which they are attached may form a 3- to 7-membered saturated or unsaturated, optionally substituted cyclic group; and R.sup.5 is independently optionally substituted C.sub.1-C.sub.4 alkyl. The present invention further relates to salts, solvates and prodrugs of such compounds, to pharmaceutical compositions comprising such compounds, and to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially by the inhibition of NLRP3.

##STR00001##

Claims

1. A compound of formula (I): ##STR00464## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Q is selected from O or S; R.sup.1 is a saturated or unsaturated hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include cyclic groups, wherein the hydrocarbyl group may optionally be substituted, and wherein the hydrocarbyl group may optionally include one or more heteroatoms N, O or S in its carbon skeleton; R.sup.2 is a cyclic group substituted at the and positions, wherein the substituent at the -position is a monovalent heterocyclic group or a monovalent aromatic group, wherein a ring atom of the heterocyclic or aromatic group is directly attached to the -ring atom of the cyclic group, wherein the heterocyclic or aromatic group may optionally be substituted, and wherein the cyclic group may optionally be further substituted; R.sup.3 is hydrogen, halogen, OH, NH.sub.2, CN, R.sup.5, OR.sup.5, NHR.sup.5 or N(R.sup.5).sub.2; R.sup.4 is hydrogen, halogen, OH, NH.sub.2, CN, R.sup.5, OR.sup.5, NHR.sup.5 or N(R.sup.5).sub.2; or R.sup.3 and R.sup.4 together with the carbon atom to which they are attached may form a 3- to 7-membered saturated or unsaturated cyclic group, wherein the cyclic group may optionally be substituted; and R.sup.5 is independently optionally substituted C.sub.1-C.sub.4 alkyl.

2. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is a 4- to 10-membered cyclic group, wherein the cyclic group may optionally be substituted.

3. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is a C.sub.1-C.sub.15 alkyl, C.sub.2-C.sub.15 alkenyl, C.sub.2-C.sub.15 alkynyl or C.sub.3-C.sub.6 cycloalkyl group, all of which may optionally be substituted, and all of which may optionally include one, two or three heteroatoms N, O or S in their carbon skeleton.

4. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is an optionally substituted phenyl group or an optionally substituted benzyl group.

5. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is a hydrocarbyl group, wherein the hydrocarbyl group may be straight-chained or branched, or be or include cyclic groups, wherein the hydrocarbyl group may optionally be substituted, and wherein the hydrocarbyl group includes one or more heteroatoms N or O in its carbon skeleton or is substituted with one or more heteroatoms N or O.

6. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is substituted with one, two or three substituents independently selected from halo; CN; NO.sub.2; N.sub.3; R.sup.; OH; OR.sup.; R.sup.-halo; R.sup.CN; R.sup.NO.sub.2; R.sup.N.sub.3; R.sup.R.sup.; R.sup.OH; R.sup.OR.sup.; SH; SR.sup.; SOR.sup.; SO.sub.2H; SO.sub.2R.sup.; R.sup.SH; R.sup.SR.sup.; R.sup.SOR.sup.; R.sup.SO.sub.2H; R.sup.SO.sub.2R.sup.; NH.sub.2; NHR.sup.; N(R.sup.).sub.2; R.sup.NH.sub.2; R.sup.NHR.sup.; R.sup.N(R.sup.).sub.2; CHO; COR.sup.; COOR.sup.; OCOR.sup.; R.sup.CHO; R.sup.COR.sup.; R.sup.COOR.sup.; R.sup.OCOR.sup.; CONH.sub.2; CONHR.sup.; CON(R.sup.).sub.2; R.sup.CONH.sub.2; R.sup.CONHR.sup.; R.sup.CON(R.sup.).sub.2; a C.sub.3-C.sub.7 cycloalkyl group optionally substituted with one or more C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl groups; a C.sub.3-C.sub.7 cycloalkenyl group optionally substituted with one or more C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl groups; ##STR00465## oxo (O); a C.sub.1-C.sub.4 alkylene bridge; or a C.sub.2-C.sub.4 alkylene bridge; wherein each R.sup. is independently selected from C.sub.1-C.sub.3 alkylene; wherein each R.sup. is independently selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.3-C.sub.6 cyclic group, and wherein any R.sup. may optionally be substituted with one or more C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.7 cycloalkyl, O(C.sub.1-C.sub.4 alkyl), halo, OH, CN, CCH, oxo (O), or 4- to 6-membered heterocyclic group; wherein each R.sup. is independently selected from hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 haloalkyl, CO(C.sub.1-C.sub.3 alkyl) or C.sub.3-C.sub.6 cycloalkyl; wherein each R.sup. is independently selected from hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl or C.sub.1-C.sub.3 alkoxy; wherein each m is independently selected from 1, 2 or 3; and wherein each n is independently selected from 1, 2 or 3.

7. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the ,-substituted cyclic group of R.sup.2 is a 5- or 6-membered cyclic group, wherein the cyclic group may optionally be further substituted.

8. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the monovalent heterocyclic or aromatic group at the -position of the cyclic group of R.sup.2 is phenyl or a 5- or 6-membered heterocyclic group, all of which may optionally be substituted.

9. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the monovalent heterocyclic or aromatic group at the -position of the cyclic group of R.sup.2 is phenyl, pyridinyl, pyrimidinyl or pyrazolyl, all of which may optionally be substituted with one or two substituents independently selected from halo, OH, NH.sub.2, CN, C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 alkynyl, C.sub.1-C.sub.3 haloalkyl, O(C.sub.1-C.sub.3 alkyl), NH(C.sub.1-C.sub.3 alkyl) or N(C.sub.1-C.sub.3 alkyl).sub.2.

10. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the ,-substituted cyclic group of R.sup.2 is substituted at a position other than with one or two substituents independently selected from halo, CN, R.sup., OR.sup. or COR.sup. groups, wherein each R.sup. is independently selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.3-C.sub.6 cyclic group, and wherein each R.sup. is optionally further substituted with one or more halo groups.

11. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the ,-substituted cyclic group of R.sup.2 is substituted with a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring fused to the ,-substituted cyclic group of R.sup.2 across the , positions.

12. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.3 and R.sup.4 are hydrogen.

13. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein Q is O.

14. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the compound is selected from the group consisting of: ##STR00466## ##STR00467## ##STR00468## ##STR00469## ##STR00470## ##STR00471## ##STR00472## ##STR00473## ##STR00474## ##STR00475## ##STR00476## ##STR00477## ##STR00478## ##STR00479## ##STR00480## ##STR00481## ##STR00482## ##STR00483## ##STR00484## ##STR00485## ##STR00486## ##STR00487## ##STR00488## ##STR00489## ##STR00490## ##STR00491## ##STR00492## ##STR00493## ##STR00494## ##STR00495## ##STR00496## ##STR00497## ##STR00498## ##STR00499## ##STR00500## ##STR00501## ##STR00502## ##STR00503## ##STR00504##

15. (canceled)

16. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, and a pharmaceutically acceptable excipient.

17. The pharmaceutical composition as claimed in claim 16, wherein the pharmaceutical composition is a topical pharmaceutical composition.

18. (canceled)

19. A method of treating or preventing a disease, disorder or condition in a subject, the method comprising the step of administering an effective amount of the compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1 to the subject, thereby treating or preventing the disease, disorder or condition, optionally wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

20. The method as claimed in claim 19, wherein the disease, disorder or condition is selected from: (i) inflammation; (ii) an auto-immune disease; (iii) cancer; (iv) an infection; (v) a central nervous system disease; (vi) a metabolic disease; (vii) a cardiovascular disease; (viii) a respiratory disease; (ix) a liver disease; (x) a renal disease; (xi) an ocular disease; (xii) a skin disease; (xiii) a lymphatic condition; (xiv) a psychological disorder; (xv) graft versus host disease; (xvi) allodynia; and (xvii) any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

21. The method as claimed in claim 19, wherein the disease, disorder or condition is selected from: (i) cryopyrin-associated periodic syndromes (CAPS); (ii) Muckle-Wells syndrome (MWS); (iii) familial cold autoinflammatory syndrome (FCAS); (iv) neonatal onset multisystem inflammatory disease (NOMID); (v) familial Mediterranean fever (FMF); (vi) pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA); (vii) hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); (viii) Tumour Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (TRAPS); (ix) systemic juvenile idiopathic arthritis; (x) adult-onset Still's disease (AOSD); (xi) relapsing polychondritis; (xii) Schnitzler's syndrome; (xiii) Sweet's syndrome; (xiv) Behcet's disease; (xv) anti-synthetase syndrome; (xvi) deficiency of interleukin 1 receptor antagonist (DIRA); and (xvii) haploinsufficiency of A20 (HA20).

22. (canceled)

23. The method as claimed in claim 19, wherein the compound is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

24. A method of inhibiting NLRP3 in a subject, comprising administering the compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1 to the subject thereby inhibiting NLRP3.

25. A method of analysing inhibition of NLRP3 or an effect of inhibition of NLRP3 by a compound, comprising contacting a cell or non-human animal with the compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, and analysing inhibition of NLRP3 or an effect of inhibition of NLRP3 in the cell or non-human animal by the compound.

Description

EXAMPLESCOMPOUND SYNTHESIS

[0285] All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

Abbreviations

[0286] 2-MeTHF 2-methyltetrahydrofuran [0287] Ac.sub.2O acetic anhydride [0288] AcOH acetic acid [0289] aq aqueous [0290] Boc tert-butyloxycarbonyl [0291] br broad [0292] Cbz carboxybenzyl [0293] CDI 1,1-carbonyl-diimidazole [0294] conc concentrated [0295] d doublet [0296] DABCO 1,4-diazabicyclo[2.2.2]octane [0297] DAST diethylaminosulfur trifluoride [0298] DCE 1,2-dichloroethane, also called ethylene dichloride [0299] DCM dichloromethane [0300] DIPEA N,N-diisopropylethylamine, also called Hnig's base [0301] DMA dimethylacetamide [0302] DMAP 4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine [0303] DME dimethoxyethane [0304] DMF N,N-dimethylformamide [0305] DMSO dimethyl sulfoxide [0306] EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide [0307] eq or equiv equivalent [0308] (ES.sup.+) electrospray ionization, positive mode [0309] Et ethyl [0310] EtOAc ethyl acetate [0311] EtOH ethanol [0312] h hour(s) [0313] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate [0314] HPLC high performance liquid chromatography [0315] LC liquid chromatography [0316] m multiplet [0317] m-CPBA 3-chloroperoxybenzoic acid [0318] Me methyl [0319] MeCN acetonitrile [0320] MeOH methanol [0321] (M+H).sup.+ protonated molecular ion [0322] MHz megahertz [0323] min minute(s) [0324] MS mass spectrometry [0325] Ms mesyl, also called methanesulfonyl [0326] MsCl mesyl chloride, also called methanesulfonyl chloride [0327] MTBE methyl tert-butyl ether, also called tert-butyl methyl ether [0328] m/z mass-to-charge ratio [0329] NaHMDS sodium hexamethyldisilazide, also called sodium bis(trimethylsilyl)amide [0330] NaO.sup.tBu sodium tert-butoxide [0331] NBS 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide [0332] NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide [0333] NMP N-methylpyrrolidine [0334] NMR nuclear magnetic resonance (spectroscopy) [0335] Pd(OAc).sub.2 palladium acetate [0336] Pd(dba).sub.2 bis(dibenzylideneacetone) palladium(0) [0337] Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone) dipalladium(0) [0338] Pd(dppf)Cl.sub.2 [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(II) [0339] PE petroleum ether [0340] Ph phenyl [0341] PMB p-methoxybenzyl, also called 4-methoxybenzyl [0342] prep-HPLC preparative high performance liquid chromatography [0343] prep-TLC preparative thin layer chromatography [0344] PTSA p-toluenesulfonic acid [0345] q quartet [0346] RP reversed phase [0347] RT room temperature [0348] s singlet [0349] sat saturated [0350] SCX solid supported cation exchange (resin) [0351] SEM 2-(trimethylsilyl)ethoxymethyl [0352] sept septuplet [0353] t triplet [0354] T3P propylphosphonic anhydride [0355] TBME tert-butyl methyl ether, also called methyl tert-butyl ether [0356] TEA triethylamine [0357] TFAA 2,2,2-trifluoroacetic acid anhydride [0358] TFA 2,2,2-trifluoroacetic acid [0359] THF tetrahydrofuran [0360] TLC thin layer chromatography [0361] TMSCl trimethylsilyl chloride [0362] wt % weight percent or percent by weight [0363] XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene [0364] Xphos 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl [0365] XtalFluor-E (diethylamino)difluorosulfonium tetrafluoroborate

EXPERIMENTAL METHODS

Analytical Methods

[0366] NMR spectra were recorded at 300, 400 or 500 MHz with chemical shifts reported in parts per million. Spectra were measured at 298 K, unless indicated otherwise, and were referenced relative to the solvent resonance. Spectra were collected using one of the machines below: [0367] An Agilent VNMRS 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, indirect detection probe and direct drive console including PFG module. [0368] An Agilent MercuryPlus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, 4 nuclei auto-switchable probe and Mercury plus console. [0369] A Bruker Avance III spectrometer at 400 MHz fitted with a BBO 5 mm liquid probe. [0370] A Bruker 400 MHz spectrometer using ICON-NMR, under TopSpin program control. [0371] A Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe.

[0372] HPLC and LC-MS were recorded on an Agilent 1290 series with UV detector and HP 6130 MSD mass detector. Mobile phase A: ammonium acetate (10 mM); water/MeOH/acetonitrile (900:60:40); mobile phase B: ammonium acetate (10 mM); water/MeOH/acetonitrile (100:540:360); column, Waters XBridge BEH C18 XP (2.150 mm, 2.5 m).

TABLE-US-00001 Pump flow: 0.6 mL/min UV detection: 215, 238 nm Injection volume: 0.2 L Run time: 4.0 min Column temperature: 35 C. Mass detection: API-ES +ve and ive

[0373] Pump Program:

TABLE-US-00002 Gradient Time (min) % A % B 0.0 80 20 0.5 80 20 2.0 0 100

[0374] Alternatively LC-MS were recorded using SHIMADZU LCMS-2020, Agilent 1200 LC/G1956A MSD and Agilent 1200\G6110A, or Agilent 1200 LC & Agilent 6110 MSD. Mobile Phase: A: 0.025% NH.sub.3.H.sub.2O in water (v/v); B: Acetonitrile. Column: Kinetex EVO C18 2.130 mm, 5 m.

[0375] Reversed Phase HPLC Conditions for the LCMS Analytical Methods

[0376] Methods 1a and 1b:

[0377] Waters Xselect CSH C18 XP column (4.630 mm, 2.5 m) at 40 C.; flow rate 2.5-4.5 mL min-1 eluted with a H.sub.2O-MeCN gradient containing either 0.1% v/v formic acid (Method 1a) or 10 mM NH.sub.4HCO.sub.3 in water (Method 1b) over 4 min employing UV detection at 254 nm.

[0378] Method 1c:

[0379] Agilent 1290 series with UV detector and HP 6130 MSD mass detector using Waters XBridge BEH C18 XP column (2.150 mm, 2.5 m) at 35 C.; flow rate 0.6 mL/min; mobile phase A: ammonium acetate (10 mM); water/MeOH/acetonitrile (900:60:40); mobile phase B: ammonium acetate (10 mM); water/MeOH/acetonitrile (100:540:360); over 4 min employing UV detection at 215 and 238 nm.

[0380] Reversed Phase HPLC Conditions for the UPLC Analytical Methods

[0381] Methods 2a and 2b:

[0382] Waters BEH C18 (2.130 mm, 1.7 m) at 40 C.; flow rate 0.77 mL min-1 eluted with a H.sub.2O-MeCN gradient containing either 0.1% v/v formic acid (Method 2a) or 10 mM NH.sub.4HCO.sub.3 in water (Method 2b) over 3 min employing UV detection at 254 nm.

[0383] Purification Method 1

[0384] Automated reversed phase column chromatography was carried out using a Buchi Sepracore X50 system driven by a C-605 pump module, C-620 Sepracore control package, C-640 UV photometer detection unit and C-660 fraction collector.

[0385] Revelis C18 reversed-phase 12 g cartridge

TABLE-US-00003 Carbon loading 18% Surface area 568 m.sup.2/g Pore diameter 65 Angstrom pH (5% slurry) 5.1 Average particle size 40 m

[0386] The column was conditioned before use with MeOH (5 min), then brought to H.sub.2O (in 5 min) and kept 5 min at H.sub.2O. Flow rate=30 mL/min.

[0387] Separation Runs:

TABLE-US-00004 Time (min) A: water (%) B: MeOH (%) 0 100 0 5 100 0 30 30 70 30.1 0 100 35 0 100

[0388] Detection wavelength: 215, 235, 254 and 280 nm. Before each new run, the cartridge was cleaned using the conditioning method.

[0389] Purification Method 2

[0390] Preparative column chromatography was carried out using a Waters prep system driven by a 2767 Sample Manager, SFO System Fluidics Organizer, 515 HPLC Pumps, 2545 Binary Gradient Module, 2998 Photodiode Array Detector, SQD Detector 2 with ESI mass. Mobile phase ACD: acetonitrile; mobile phase A: ammonium acetate (10 mM); mobile phase B: acetonitrile; column, XSelect CSH Prep C18 OBD (10030 mm; 5 m).

TABLE-US-00005 Pump flow: 40 mL/min Injection volume: 1.5 mL Run time: 15.0 min Column temperature: not controlled Mass detection: API-ES +ve and ive

[0391] Pump Program:

TABLE-US-00006 Flow (ml/min) Flow (ml/min) Time (min) Bin. pump ACD pump % A % B 0.0 22 4 85 15 2.0 38 2 85 15 2.5 38 2 85 15 10.0 38 2 65 35 10.1 38 2 5 95 12.0 38 2 5 95 12.1 38 2 85 15 15.0 38 2 85 15

[0392] Purification Method 3 (Acidic Prep)

[0393] Preparative reversed phase HPLC was carried out using a Waters X-Select CSH column C18, 5 m (1950 mm), flow rate 28 mL min-1 eluting with a H.sub.2O-MeCN gradient containing 0.1% v/v formic acid over 6.5 min using UV detection at 254 nm. Gradient information: 0.0-0.2 min, 20% MeCN; 0.2-5.5 min, ramped from 20% MeCN to 40% MeCN; 5.5-5.6 min, ramped from 40% MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

[0394] Purification Method 4 (Basic Prep)

[0395] Preparative reversed phase HPLC was carried out using a Waters X-Bridge Prep column C18, 5 m (1950 mm), flow rate 28 mL min-1 eluting with a 10 mM NH.sub.4HCO.sub.3-MeCN gradient over 6.5 min using UV detection at 254 nm. Gradient information: 0.0-0.2 min, 10% MeCN; 0.2-5.5 min, ramped from 10% MeCN to 40% MeCN; 5.5-5.6 min, ramped from 40% MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

[0396] Alternatively automated reversed phase HPLC column chromatography purification was carried out using:

(i) a Gilson GX-281 system driven by a Gilson-322 pump module, Gilson-156 UV photometer detection unit and Gilson-281 fraction collector. Detection wavelength: 220 nm and 254 nm and 215 nm.
(ii) a Gilson GX-215 system driven by a LC-20AP pump module, SPD-20A UV photometer detection unit and Gilson-215 fraction collector. Detection wavelength: 220 nm and 254 nm and 215 nm.
(iii) a TELEDYNE ISCO CombiFlash Rf+150. Detection wavelength: 220 nm and 254 nm and 215 nm.
(iv) a Shimadzu CBM-20A system driven by LC-20AP pump module, SPD-20A UV photometer detection unit and FRC-10A fraction collector. Detection wavelength: 220 nm and 254 nm and 215 nm.

SYNTHESIS OF INTERMEDIATES

Intermediate A1: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid, trifluoroacetic acid salt

Step A: 2-Bromo-4-fluoro-6-(prop-1-en-2-yl)aniline

[0397] ##STR00090##

[0398] 2,6-Dibromo-4-fluoroaniline (10.0 g, 37.2 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (6.87 g, 40.9 mmol) and potassium carbonate (15.4 g, 112 mmol) were dissolved in dioxane (8 mL) and water (4 mL) and degassed four times under argon atmosphere. Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (1.52 g, 1.86 mmol) was added and the mixture was refluxed for 48 hours. Water (20 mL) and ethyl acetate (40 mL) were added and the layers were separated. The aqueous layer was extracted with ethyl acetate (30 mL). The combined organic layers were dried over sodium sulfate, evaporated to dryness and subjected to column chromatography (SiO.sub.2, heptanes with 15% ethyl acetate) to yield the title compound (3.5 g, 41%) as a light brown oil.

[0399] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.10 (dd, 1H), 6.76 (dd, 1H), 5.36 (bs, 1H), 5.08 (bs, 1H), 4.05 (bs, 2H), 2.05 (s, 3H).

Step B: 4-Fluoro-2-(2-methoxypyridin-4-yl)-6-(prop-1-en-2-yl)aniline

[0400] ##STR00091##

[0401] 2-Bromo-4-fluoro-6-(prop-1-en-2-yl)aniline (8.56 g, 37.2 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (10.5 g, 44.6 mmol) were dissolved in dioxane (10 mL) under N.sub.2 atmosphere. Potassium carbonate (15.4 g, 112 mmol) in water (10 mL) was added. Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (1.52 g, 1.86 mmol) was added and the mixture was stirred overnight at reflux. The dioxane was largely removed by rotary evaporation. Ethyl acetate (100 mL) was added and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to dryness to yield the title compound (8.0 g, 83%) as a brown oil.

[0402] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.20 (d, 1H), 7.00 (m, 2H), 6.82 (s, 1H), 6.72 (d, 1H), 5.34 (bs, 1H), 5.09 (bs, 1H), 3.98 (s, 3H), 3.80 (bs, 2H), 2.05 (s, 3H).

[0403] LCMS: m/z 259 (M+H).sup.+ (ES.sup.+).

Step C: 4-Fluoro-2-(2-methoxypyridin-4-yl)-6-(isopropyl)aniline

[0404] ##STR00092##

[0405] 4-Fluoro-2-(2-methoxypyridin-4-yl)-6-(prop-1-en-2-yl)aniline (8.0 g, 31 mmol) was dissolved in methanol (50 mL). Pd/C (0.4 g, 0.4 mmol) was added and the mixture was stirred overnight under H.sub.2 atmosphere. The product was filtered over Celite and subjected to column chromatography (SiO.sub.2, heptanes with 15% ethyl acetate) yielding the title compound (7.9 g, 99%) as a colourless oil.

[0406] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.21 (d, 1H), 6.98 (dd, 1H), 6.92 (dd, 1H), 6.82 (s, 1H), 6.70 (dd, 1H), 3.98 (s, 3H), 3.61 (bs, 2H), 2.91 (m, 1H), 1.25 (d, 6H).

[0407] LCMS: m/z 261 (M+H).sup.+ (ES.sup.+).

Step D: 4-(2-Bromo-5-fluoro-3-isopropylphenyl)-2-methoxypyridine

[0408] ##STR00093##

[0409] 4-Fluoro-2-(2-methoxypyridin-4-yl)-6-(isopropyl)aniline (200 mg, 768 mol) in acetonitrile (12 mL) at 0 C. was treated with concentrated HBr (1.3 g) in water (1 mL). Sodium nitrite (58.3 mg, 845 mol) in water (1 mL) was added and the mixture was stirred at 0 C. for 45 minutes. Copper(I) bromide (110 mg, 768 mol) and copper(II) bromide (172 mg, 768 mol) were added and the mixture was allowed to reach room temperature over 2 hours. The mixture was poured into saturated sodium carbonate solution (50 mL). The mixture was extracted with DCM (250 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness in vacuo to yield the title compound (160 mg, 64%) as a brown oil.

[0410] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.20 (d, 1H), 7.02 (dd, 1H), 6.85 (d, 1H), 6.82 (dd, 1H), 6.73 (s, 1H), 3.98 (s, 3H), 3.42 (m, 1H), 1.24 (d, 6H).

[0411] LCMS: m/z 324 (M+H).sup.+ (ES.sup.+).

Step E: (2-(tert-Butoxy)-2-oxoethyl) zinc (II) bromide

[0412] ##STR00094##

[0413] To a mixture of Zn (55 g, 841.11 mmol, 2.98 eq) in THF (550 mL) was added TMSCl (3.06 g, 28.20 mmol, 0.1 eq) and 1,2-dibromoethane (5.30 g, 28.20 mmol, 0.1 eq) under N.sub.2 atmosphere. The mixture was refluxed for 1 hour. After cooling to 40 C., tert-butyl 2-bromoacetate (55 g, 281.97 mmol, 1 eq) was added and the mixture was refluxed for 2 hours. The mixture was cooled, decanted and the supernatant was used into the next step without further purification (crude).

Step F: tert-Butyl 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate

[0414] ##STR00095##

[0415] 4-(2-Bromo-5-fluoro-3-isopropylphenyl)-2-methoxypyridine (3-1, 9.6 mmol) was dissolved in THF (25 mL) under N.sub.2 atmosphere. Pd.sub.2dba.sub.3 (chloroform adduct) (0.55 g, 0.53 mmol) and Xphos (0.50 g, 1.1 mmol) were added. (2-(tert-Butoxy)-2-oxoethyl) zinc (II) bromide (5.5 g, 21 mmol) in THF (20 ml) (prepared in step E) was added and the mixture was heated to 80 C. and stirred overnight. Then the mixture was cooled to room temperature, filtered over Celite and evaporated to dryness in vacuo. The crude product was subjected to column chromatography (SiO.sub.2, heptanes with a 0 to 20% gradient of ethyl acetate) yielding the title compound (1.7 g, 48%) as a colourless oil.

[0416] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.19 (d, 1H), 7.03 (dd, 1H), 6.82 (d, 1H), 6.78 (dd, 1H), 6.68 (s, 1H), 3.98 (s, 3H), 3.42 (s, 2H), 3.02 (m, 1H), 1.41 (s, 9H), 1.23 (d, 6H).

[0417] LCMS: m/z 360 (M+H).sup.+ (ES.sup.+).

Step G: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid, trifluoroacetic acid salt

[0418] ##STR00096##

[0419] tert-Butyl 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate (3.4 g, 9.5 mmol) was dissolved in DCM (20 mL) and TFA (15 g, 10 mL, 0.13 mol) and stirred for 6 hours at room temperature. The mixture was evaporated to dryness, yielding the title compound (3.9 g, 99%) as a colourless oil.

[0420] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.19 (d, 1H), 7.03 (dd, 1H), 6.81 (d, 1H), 6.78 (dd, 1H), 6.68 (s, 1H), 3.98 (s, 3H), 3.59 (s, 2H), 3.02 (m, 1H), 1.23 (d, 6H).

[0421] LCMS: m/z 302 (MH).sup. (ES.sup.).

Intermediate A2: 2-(5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetyl chloride

Step A: 5-(Benzyloxy)-4-bromo-2,3-dihydro-1H-indene

[0422] ##STR00097##

[0423] To a solution of 4-bromo-2,3-dihydro-1H-inden-5-ol (1.36 g, 6.38 mmol, 1 eq) (Hunsberger et al., JACS, 1955, vol. 77(9), pages 2466-2475) in dimethylformamide (35 mL) was added potassium carbonate (1.76 g, 12.8 mmol, 2 eq) and benzyl bromide (0.83 mL, 7.02 mmol, 1.1 eq). The reaction mixture was heated to 60 C. After stirring for 1.5 hours, the mixture was cooled to room temperature and diluted with diethyl ether. The organic layer was washed 4 times with water, once with brine, dried over sodium sulfate and then concentrated in vacuo to afford the title compound (1.83 g, 6.04 mmol, 94%).

[0424] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.52-7.46 (m, 2H), 7.42-7.29 (m, 3H), 7.03 (d, 1H), 6.72 (d, 1H), 5.13 (s, 2H), 2.96 (t, 4H), 2.10 (p, 2H).

Step B: tert-Butyl 2-(5-(benzyloxy)-2,3-dihydro-1H-inden-4-yl)acetate

[0425] ##STR00098##

[0426] A solution of 5-(benzyloxy)-4-bromo-2,3-dihydro-H-indene (1.83 g, 6.04 mmol, 1 eq) in anhydrous tetrahydrofuran (50 mL) was bubbled through with nitrogen for 20 minutes. To the degassed solution was added tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (312 mg, 302 mol, 0.05 eq) and dicyclohexyl(2,4,6-triisopropyl-[1,1-biphenyl]-2-yl)phosphane (288 mg, 604 mol, 0.1 eq). The reaction mixture was stirred for 30 minutes at room temperature. After that, (2-(tert-butoxy)-2-oxoethyl) zinc (II) bromide (Intermediate A1, Step E) in THF (0.55 molar, 22 mL, 12.1 mmol, 2 eq) was added and the reaction mixture was heated in a sand bath at 70 C. After stirring for 1 hour, the reaction mixture was cooled to room temperature and then diluted with diethyl ether. The reaction mixture was washed twice with saturated ammonium chloride, once with brine, dried over sodium sulfate, filtered and then concentrated in vacuo. The crude product was submitted to normal phase flash chromatography using heptane and ethyl acetate as eluent to afford the title compound (1.82 g, 5.38 mmol, 89%).

[0427] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.44 (d, 2H), 7.40-7.29 (m, 3H), 7.05 (d, 1H), 6.72 (d, 1H), 5.06 (s, 2H), 3.62 (s, 2H), 2.87 (t, 4H), 2.08 (p, 2H), 1.40 (s, 9H).

Step C: tert-Butyl 2-(5-hydroxy-2,3-dihydro-1H-inden-4-yl)acetate

[0428] ##STR00099##

[0429] A solution of tert-butyl 2-(5-(benzyloxy)-2,3-dihydro-1H-inden-4-yl)acetate (1.82 g, 5.38 mmol, 1 eq) in 2,2,2-trifluoroethanol (50 mL) was bubbled through with nitrogen for 20 minutes. After that, Pd/C (10 wt % loading, matrix activated carbon support, 0.57 g, 538 mol, 0.1 eq) was added and the flask was charged with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere. After 1.5 hours of stirring, another batch of Pd/C (10 wt % loading, matrix activated carbon support, 0.57 g, 538 mol, 0.1 eq) was added. After stirring over the weekend, the reaction mixture was filtered over Celite, and the residue was washed extensively with ethyl acetate. The filtrates were combined and concentrated in vacuo to afford the title compound (1.28 g, 5.15 mmol, 95%).

[0430] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.33 (bs, 1H), 7.01 (d, 1H), 6.76 (d, 1H), 3.57 (s, 2H), 2.88 (td, 4H), 2.15-1.96 (m, 2H), 1.46 (s, 9H).

Step D: tert-Butyl 2-(5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-inden-4-yl)acetate

[0431] ##STR00100##

[0432] A solution of tert-butyl 2-(5-hydroxy-2,3-dihydro-1H-inden-4-yl)acetate (1.28 g, 5.15 mmol, 1 eq) and triethylamine (1.4 mL, 10.3 mmol, 2 eq) in dichloromethane (50 mL) was cooled in an ice bath. To the cooled greenish solution was added dropwise triflic anhydride (0.87 mL, 5.15 mmol, 1 eq). After complete addition, the cooling bath was removed and the reaction mixture was allowed to reach room temperature. After 1 hour of stirring, the reaction mixture was washed three times with saturated sodium bicarbonate solution, once with brine, dried over sodium sulfate, filtered and then concentrated in vacuo to afford the title compound (1.74 g, 4.57 mmol, 88%).

[0433] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.17 (d, 1H), 7.07 (d, 1H), 3.63 (s, 2H), 2.92 (dt, 4H), 2.14 (p, 2H), 1.44 (s, 9H).

Step E: tert-Butyl 2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetate

[0434] ##STR00101##

[0435] A suspension of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.08 g, 4.57 mmol, 1 eq), tert-butyl 2-(5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-inden-4-yl)acetate (1.74 g, 4.57 mmol, 1 eq) and potassium carbonate (1.90 g, 13.7 mmol, 3 eq) in 1,4-dioxane (25 mL) was bubbled through with nitrogen for 20 minutes. After that, [1,1-bis(diphenylphosphino)ferrocene] dichloro palladium (II) (167 mg, 229 mol, 0.05 eq) was added and the reaction mixture was heated to 80 C. After stirring overnight, another batch of [1,1-bis(diphenylphosphino)ferrocene] dichloro palladium (II) (167 mg, 229 mol, 0.05 eq) was added and the temperature of the reaction mixture was increased to 100 C. After 2 more hours of stirring, another batch of [1,1-bis(diphenylphosphino)ferrocene] dichloro palladium (II) (167 mg, 229 mol, 0.05 eq) was added. After stirring for 20 more hours, another batch of [1,1-bis(diphenylphosphino)ferrocene] dichloro palladium (II) (167 mg, 229 mol, 0.05 eq) was added. After 3 more hours of stirring, the reaction mixture was cooled to room temperature and then filtered. The residue was washed with ethyl acetate and dichloromethane. The filtrates were combined and concentrated in vacuo. The crude product was submitted to normal phase flash chromatography using heptane and ethyl acetate as eluent to afford the title compound (358 mg, 1.05 mmol, 23%).

[0436] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.16 (d, 1H), 7.19 (d, 1H), 7.03 (d, 1H), 6.86 (dd, 1H), 6.71 (s, 1H), 3.97 (d, 3H), 3.46 (s, 2H), 2.99 (t, 2H), 2.90 (t, 2H), 2.13 (p, 2H), 1.42 (s, 9H).

Step F: 2-(5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid, trifluoroacetic acid salt

[0437] ##STR00102##

[0438] A solution of tert-butyl 2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetate (172 mg, 507 mol, 1 eq) in trifluoroacetic acid (1 mL, 13 mmol, 26 eq) was stirred at room temperature. After for 20 hours, more trifluoroacetic acid (0.5 mL, 6.5 mmol, 13 eq) was added. After 2 more hours, the solution was concentrated in vacuo. The crude product was suspended in toluene and then concentrated again; this was performed 3 times to afford the title compound (180 mg, 506 mol, 89%).

[0439] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.23 (dd, 1H), 7.32-7.23 (m, 1H), 7.23-6.99 (m, 3H), 4.07 (s, 3H), 3.59 (s, 2H), 2.97 (dt, 4H), 2.14 (p, 2H).

Step G: 2-(5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetylchloride

[0440] ##STR00103##

[0441] To a solution of 2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid, trifluoroacetic acid salt (219 mg, 0.55 mmol, 1 eq) in anhydrous dichloromethane (10 mL) was added one drop of dimethylformamide and then dropwise oxalyl chloride (145 L, 1.65 mmol, 3 eq) at room temperature. After stirring for 2 hours, the reaction mixture was concentrated in vacuo. The crude product was used in the next step without any purification.

Intermediate A3: 2-(5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetyl chloride

Step A: tert-Butyl 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-4-yl)acetate

[0442] ##STR00104##

[0443] A solution of tert-butyl 2-(5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-inden-4-yl)acetate (Intermediate A2, Step D) (4.64 g, 12.2 mmol, 1 eq) in 1,4-dioxane (61 mL) was degassed with nitrogen. After that, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.3 mL, 36.6 mmol, 3.9 eq), triethylamine (10 mL, 73.2 mmol, 6.0 eq) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) adduct (498 mg, 610 mol, 0.05 eq) was added. The reaction mixture was heated in a sand bath set at 100 C. After stirring overnight, the reaction mixture was concentrated in vacuo. The crude product was submitted to normal phase flash chromatography using heptane and ethyl acetate as eluent to afford the title compound (3.79 g, 10.5 mmol, 86%).

[0444] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.63 (d, 1H), 7.13 (d, 1H), 3.92 (d, 2H), 2.90 (dt, 4H), 2.04 (p, 2H), 1.42 (s, 9H), 1.32 (s, 12H).

Step B: tert-Butyl 2-(5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetate

[0445] ##STR00105##

[0446] A solution of tert-butyl 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-4-yl)acetate (3.74 g, 10.4 mmol, 1 eq) and 4-bromopicolinonitrile (2.29 g, 12.5 mmol, 1.2 eq) in acetonitrile (74 mL) and water (30 mL) was degassed with nitrogen. Then sodium carbonate (1.77 g, 16.7 mmol, 1.6 eq) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) adduct (852 mg, 1.04 mmol, 0.1 eq) were added. The reaction mixture was heated in a sand bath set at 80 C. After 50 minutes, the reaction mixture was cooled to room temperature, diluted with water and then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and then concentrated in vacuo. The crude product was submitted to normal phase flash chromatography using ethyl acetate and heptane as eluent to afford the title compound (2.63 g, 7.86 mmol, 75%).

[0447] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.71 (dd, 1H), 7.72 (dd, 1H), 7.52 (dd, 1H), 7.24 (d, 1H), 7.01 (d, 1H), 3.42 (s, 2H), 3.01 (t, 2H), 2.92 (t, 2H), 2.15 (p, 2H), 1.43 (s, 9H).

Step C: 2-(5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid TFA salt and 2-(5-(2-carbamoylpyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid TFA salt in Ratio 7:3

[0448] ##STR00106##

[0449] To a solution of tert-butyl 2-(5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetate (2.63 g, 7.86 mmol, 1 eq) in dichloromethane (20 mL) was added trifluoroacetic acid (20 mL, 0.26 mol, 33 eq). The reaction mixture was stirred at room temperature for 2.5 hours and then toluene (40 mL) was added. The reaction mixture was concentrated to about 40 mL, and then again toluene (40 mL) was added; this process was done twice. Then all solvents were evaporated in vacuo to afford 2-(5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid (2.92 g, 94%) as a 7:3 mixture with 2-(5-(2-carbamoylpyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid both as the TFA salt.

[0450] .sup.1H NMR (of 2-(5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid) (300 MHz, CDCl.sub.3) 8.78 (d, 1H), 7.74 (d, 1H), 7.58 (dd, 1H), 7.34-7.25 (m, 1H), 7.03 (d, 1H), 3.58 (d, 2H), 3.04 (d, 2H), 2.94 (t, 2H), 2.17 (p, 2H).

Step D: 2-(5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetylchloride

[0451] ##STR00107##

[0452] To a solution of 2-(5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid (non salt form) (34 mg, 0.12 mmol, 1 eq) in anhydrous dichloromethane (2 mL) was added one drop of dimethylformamide and after that dropwise oxalyl chloride (32 L, 0.37 mmol, 3 eq) at room temperature. After stirring for 1 hour, the volatiles were removed in vacuo and the crude product was used for the following step without any purification.

Intermediate A4: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride

[0453] ##STR00108##

[0454] 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid, TFA salt (Intermediate A1) (61 mg, 0.2 mmol) was stirred in DCM (10 mL) and one drop of dimethylformamide was added followed by the dropwise addition of oxalylchloride (88 L, 1 mmol). The solution was stirred at room temperature for 4 hours and then concentrated thoroughly to afford the title compound (65 mg, 99%) as a yellow oil.

[0455] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.04 (s, 1H), 7.23-7.11 (m, 2H), 7.04 (s, 1H), 6.88-6.75 (m, 1H), 4.40 (s, 3H), 4.08 (s, 2H), 3.17 (m, 1H), 1.27 (m, 6H).

Intermediate A5: 2-(4-Fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetyl chloride

Step A: 2-Bromo-4-fluoro-6-methoxyaniline

[0456] ##STR00109##

[0457] A solution of 4-fluoro-2-methoxyaniline (17.5 g, 0.12 mol) in DMF (200 mL) was cooled to 0 C. 1-Bromopyrrolidine-2,5-dione (22.1 g, 0.12 mol) was added in portions over 1 hour. The reaction mixture was stirred for 3 hours at 0 C. and for 40 hours at 21 C. Then the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified over silica using ethyl acetate/heptane as the eluent to afford the title compound (4 g, 15%) as a pale red oil which crystallized upon standing.

[0458] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.86 (dd, 1H), 6.54 (dd, 1H), 3.94 (s, br, 2H), 3.83 (s, 3H).

Step B: 4-Fluoro-2-methoxy-6-(prop-1-en-2-yl)aniline

[0459] ##STR00110##

[0460] A mixture of 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (18 g, 0.11 mol), cesium carbonate (36 g, 0.11 mol) and 2-bromo-4-fluoro-6-methoxyaniline (16 g, 0.073 mol) in dioxane/water (150 mL, 10/1) was purged with nitrogen. Next [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (2.5 g, 3 mmol) was added and the reaction mixture was stirred for 36 hours at 90 C. under nitrogen atmosphere. The mixture was filtered over Celite and evaporated. The residue was purified over silica using ethyl acetate/heptane as the eluent to afford the title compound (11.6 g, 86%) as a pale brown oil.

[0461] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.47 (m, 2H), 5.32 (s, 1H), 5.09 (s, 1H), 3.85 (s, 3H), 3.77 (s, br, 2H), 2.07 (s, 3H).

Step C: 4-Fluoro-2-isopropyl-6-methoxyaniline

[0462] ##STR00111##

[0463] A mixture of 4-fluoro-2-methoxy-6-(prop-1-en-2-yl)aniline (2.0 g, 11 mmol) and Pd/C (10%, 100 mg) in methanol was stirred for 36 hours under a hydrogen atmosphere. The mixture was filtered over Celite and evaporated to afford the title compound (2 g, 100%) as a pale brown oil.

[0464] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.52 (m, 2H), 3.88 (s, 3H), 3.58 (s, br, 2H), 2.95 (m, 1H), 1.29 (d, 6H).

Step D: 2-Bromo-5-fluoro-1-isopropyl-3-methoxybenzene

[0465] ##STR00112##

[0466] 4-Fluoro-2-isopropyl-6-methoxyaniline (3.084 g, 16.8 mmol) in 48% HBr (15 mL)/water (15 mL) was cooled to 5 C. A solution of sodium nitrite (1.39 g, 20 mmol) in water (10 ml) was added dropwise over 15 minutes and then the reaction mixture was stirred for 15 minutes at 0 C. The diazo mixture was added dropwise to a suspension of copper(I) bromide (2.41 g, 16.8 mmol) in 48% HBr (10 mL)/water (10 mL) at reflux. The reaction mixture was refluxed for 3 hours, and then extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified over silica using ethyl acetate/heptane as the eluent to afford the title compound (1.7 g, 41%) as a colourless oil.

[0467] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.65 (dd, 1H), 6.51 (dd, 1H), 3.88 (s, 3H), 3.48 (m, 1H), 1.22 (d, 6H).

Step E: tert-Butyl 2-(4-fluoro-2-isopropyl-6-methoxyphenyl)acetate

[0468] ##STR00113##

[0469] To 2-bromo-5-fluoro-1-isopropyl-3-methoxybenzene (1.5 g, 6.1 mmol) in THF was added Xphos (275 mg, 0.58 mmol) and the mixture was purged for 15 minutes with nitrogen. Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (300 mg, 0.29 mmol) was added and (2-(tert-butoxy)-2-oxoethyl) zinc (II) bromide (Intermediate A1, Step E) (3.2 g, 12 mmol) in THF was added dropwise. The reaction mixture was refluxed for 5 hours, poured into saturated NaHCO.sub.3 and extracted with tert-butyl methyl ether. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified over silica using ethyl acetate/heptane as the eluent to afford the title compound (1.2 g, 72%) as a pale yellow oil.

[0470] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.61 (dd, 1H), 6.46 (dd, 1H), 3.79 (s, 3H), 3.59 (s, 2H), 3.08 (m, 1H), 1.44 (s, 9H), 1.19 (d, 6H).

Step F: 2-(4-Fluoro-2-hydroxy-6-isopropylphenyl)acetic acid

[0471] ##STR00114##

[0472] A solution of tert-butyl 2-(4-fluoro-2-isopropyl-6-methoxyphenyl)acetate (0.86 g, 3.0 mmol) in dichloromethane (20 mL) was cooled to 60 C. Tribromoborane (2.3 g, 9.1 mmol) was added dropwise. The reaction mixture was stirred for 4 hours at 60 to 30 C. The dichloromethane layer was washed with NaOH (10%). The basic water layer was acidified to pH 1 with HCl (37%) and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified over silica using ethyl acetate/heptane as the eluent to afford the title compound (0.45 g, 70%) as a pale yellow oil.

[0473] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.72 (m, 2H), 3.66 (s, 2H), 2.86 (m, 1H), 1.25 (d, 6H).

Step G: Methyl 2-(4-fluoro-2-hydroxy-6-isopropylphenyl)acetate

[0474] ##STR00115##

[0475] To a solution of 2-(4-fluoro-2-hydroxy-6-isopropylphenyl)acetic acid (450 mg, 2.12 mmol) in methanol (50 mL) was added H.sub.2SO.sub.4 (50 mg, 98%) and the mixture was refluxed for 6 hours. The bulk of the methanol was evaporated. Tert-butyl methyl ether was added and the organic layer was washed with brine (2), dried over sodium sulfate, filtered and evaporated to afford the title compound (480 mg, 100%) as an oil.

[0476] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.61 (dd, 1H), 6.50 (dd, 1H), 3.76 (s, 3H), 3.71 (s, 2H), 3.15 (m, 1H), 1.20 (d, 6H).

Step H: Methyl 2-(4-fluoro-2-isopropyl-6-(((trifluoromethyl)sulfonyl)oxy)phenyl) acetate

[0477] ##STR00116##

[0478] A solution of methyl 2-(4-fluoro-2-hydroxy-6-isopropylphenyl)acetate (120 mg, 0.53 mmol) in dichloromethane (12 mL) was cooled to 0 C. Triethylamine (1 mL) and next trifluoromethanesulfonic anhydride (224 mg, 0.80 mmol) were added and the reaction mixture was stirred for 18 hours at 21 C. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and evaporated. The residue was purified over silica using ethyl acetate/heptane as the eluent to afford the title compound (130 mg, 68%) as a colourless oil.

[0479] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.07 (dd, 1H), 6.94 (dd, 1H), 3.77 (s, 2H), 3.71 (s, 3H), 3.09 (m, 1H), 1.21 (d, 6H).

Step I: Methyl 2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetate

[0480] ##STR00117##

[0481] A mixture of methyl 2-(4-fluoro-2-isopropyl-6-(((trifluoromethyl)sulfonyl)oxy)phenyl) acetate (100 mg, 0.28 mmol), cesium carbonate (91 mg, 0.28 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (114 mg, 0.56 mmol) in dioxane/water (1/10, 4 mL) was purged with nitrogen. PdC.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (20 mg, 0.28 mmol) was added and the reaction mixture was warmed for 2 hours at 130 C. in a microwave. The reaction mixture was filtered over Celite. The solvents were evaporated and the residue was purified over silica using ethyl acetate/heptane as the eluent to afford the title compound (55 mg, 69%) as an oil.

[0482] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.62 (s, br, 1H), 8.53 (s, br, 1H), 7.63 (d, 1H), 7.34 (m, 1H), 7.05 (dd, 1H), 6.79 (dd, 1H), 3.63 (s, 3H), 3.55 (s, 2H), 3.05 (m, 1H), 1.24 (d, 6H).

[0483] LCMS: m/z 288 (M+H).sup.+ (ES.sup.+).

Step J: 2-(4-Fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetic acid

[0484] ##STR00118##

[0485] A mixture of methyl 2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetate (415 mg, 1.45 mmol) and potassium hydroxide (0.19 g, 2.88 mmol) in methanol (20 mL) and water (2 mL) was refluxed for 4 hours. The solvents were evaporated and the residue was dissolved in methanol (50 mL). The solution was acidified with Amberlite IRC-86 weakly acidic ion exchange resin to pH 6, filtered and evaporated to afford the title compound (360 mg, 91%) as an off white solid.

[0486] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.77 (s, br, 1H), 8.57 (s, br, 1H), 7.76 (d, 1H), 7.47 (s, br, 1H), 7.09 (dd, 1H), 6.76 (dd, 1H), 3.49 (s, 2H), 3.18 (m, 1H), 1.28 (d, 6H).

Step K: 2-(4-Fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetyl chloride

[0487] ##STR00119##

[0488] 2-(4-Fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetic acid (50 mg, 0.18 mmol) was stirred in DCM (10 mL) and one drop of dimethylformamide was added followed by the dropwise addition of oxalylchloride (48 L, 0.55 mmol). The solution was stirred at room temperature for 4 hours and concentrated thoroughly to afford the title compound (53 mg, 99%) as a yellow oil.

[0489] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.89 (d, 1H), 8.74 (s, 1H), 8.31 (d, 1H), 8.07 (m, 1H), 7.23-7.16 (m, 1H), 6.85-6.71 (m, 1H), 4.06 (s, 2H), 3.18 (m, 1H), 1.27 (m, 6H).

Intermediate A6: 2-(4-Fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetyl chloride

Step A: 4-Fluoro-2-(pyridin-4-yl)-6-(prop-1-en-2-yl)aniline

[0490] ##STR00120##

[0491] A mixture of 2-bromo-4-fluoro-6-(prop-1-en-2-yl)aniline (Intermediate A1, Step A) (13.9 g, 36 mmol) in dioxane (150 ml) and water (20 ml) was flushed with nitrogen (gas). Cesium carbonate (18 g, 54 mmol) and PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (0.74 g, 0.91 mmol) was added and the reaction mixture was flushed with nitrogen (gas). Next 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (11 g, 54 mmol) was added and the reaction mixture was heated for 15 hours at 100 C. The dioxane was evaporated and the water layer was extracted with ethyl acetate (3). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified over silica, using ethyl acetate/heptane as the eluent to afford the title compound (6 g, 73%) as a brown oil which crystallized upon standing.

[0492] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.69 (d, 2H), 7.42 (d, 2H), 6.78 (dd, 1H), 6.72 (dd, 1H), 5.36 (s, 1H), 5.11 (s, 1H), 3.74 (bs, 2H), 2.09 (m, 3H).

Step B: 4-Fluoro-2-(pyridin-4-yl)-6-(isopropyl)aniline

[0493] ##STR00121##

[0494] 4-Fluoro-2-(pyridin-4-yl)-6-(prop-1-en-2-yl)aniline (4.2 g, 18 mmol) was dissolved in methanol (50 mL). Pd/C (10%) (0.4 g, 0.4 mmol) was added and the reaction mixture was stirred overnight under a hydrogen atmosphere. The crude product was filtered over Celite and subjected to column chromatography (SiO.sub.2, heptanes with 15% ethyl acetate). The title compound (3.8 g, 90%) was obtained as a colourless oil.

[0495] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.64 (d, 2H), 7.40 (d, 2H), 6.82 (dd, 1H), 6.76 (dd, 1H), 3.61 (bs, 2H), 2.91 (m, 1H), 1.25 (d, 6H).

[0496] LCMS: m/z 231 (M+H).sup.+ (ES.sup.+).

Step C: 4-(2-Bromo-5-fluoro-3-isopropylphenyl)pyridine

[0497] ##STR00122##

[0498] 4-Fluoro-2-(pyridin-4-yl)-6-(isopropyl)aniline (1.8 g, 7.8 mmol) in acetonitrile (100 mL) at 0 C. was treated with concentrated HBr (13 g) in water (10 mL). Sodium nitrite (583 mg, 8.45 mmol) in water (1 mL) was added and the reaction mixture was stirred at 0 C. for 45 minutes. Copper(I) bromide (1.10 g, 7.68 mmol) and copper(II) bromide (1.72 g, 7.68 mmol) were added. The reaction mixture was allowed to reach room temperature over 2 hours, poured into saturated sodium carbonate solution (300 mL), and extracted with DCM (2250 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness in vacuo. The title compound (0.85 g, 37%) was obtained as a brown oil.

[0499] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.66 (d, 2H), 7.28 (d, 2H), 7.05 (dd, 1H), 6.83 (dd, 1H), 3.42 (m, 1H), 1.25 (d, 6H).

[0500] LCMS: m/z 294 (M+H).sup.+ (ES.sup.+).

Step D: tert-Butyl 2-(4-fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetate

[0501] ##STR00123##

[0502] 4-(2-Bromo-5-fluoro-3-isopropylphenyl)pyridine (2.1 g, 7.1 mmol) was dissolved in THF (25 mL) under nitrogen atmosphere. Pd.sub.2dba.sub.3 (chloroform adduct) (0.33 g, 0.36 mmol) and Xphos (0.34 g, 0.71 mmol) were added. (2-(tert-Butoxy)-2-oxoethyl) zinc (II) bromide (Intermediate A1, Step E) (4.1 g, 16 mmol) in THF (16 ml) was added. The reaction mixture was heated to 80 C. and stirred overnight, and then cooled to room temperature, filtered over Celite and evaporated to dryness in vacuo. The crude product was subjected to column chromatography (SiO.sub.2, heptanes with a 0-20% gradient of ethyl acetate). The title compound (1.1 g, 48%) was obtained as a brown oil.

[0503] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.76 (d, 2H), 7.38 (d, 2H), 7.05 (dd, 1H), 6.78 (dd, 1H), 3.43 (s, 2H), 3.04 (m, 1H), 1.40 (s, 9H), 1.23 (d, 6H).

[0504] LCMS: m/z 274 (MtBu+2H).sup.+ (ES.sup.+).

Step E: 2-(4-Fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetic acid, trifluoroacetic acid salt

[0505] ##STR00124##

[0506] To a solution of tert-butyl 2-(4-fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetate (1.48 g, 4.49 mmol, 1 eq) in dichloromethane (11 mL) was added trifluoroacetic acid (11 mL, 0.14 mmol, 32 eq). The solution was stirred at room temperature overnight and then concentrated in vacuo to afford the title compound (2.25 g, quantitative yield).

[0507] .sup.1H NMR (300 MHz, CDCl.sub.3) 9.00 (d, 2H), 7.93 (d, 2H), 7.21 (dd, 1H), 6.81 (dd, 1H), 3.57 (s, 2H), 3.11 (p, 1H), 1.27 (d, 6H).

Step F: 2-(4-Fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetyl chloride

[0508] ##STR00125##

[0509] To a solution of 2-(4-fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetic acid (non salt form) (54 mg, 0.20 mmol, 1 eq) and one drop of dimethylformamide in anhydrous dichloromethane (8 mL) was added dropwise oxalyl chloride (53 L, 0.60 mmol, 3 eq) at room temperature. The reaction mixture was stirred for 1 hour at room temperature and then concentrated in vacuo. The crude product was used in the next step without purification.

Intermediate A7: 2-(2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) acetic acid

Step A: 4-Fluoro-2-(prop-1-en-2-yl)aniline

[0510] ##STR00126##

[0511] To a mixture of 2-bromo-4-fluoroaniline (39 g, 205.25 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (36.21 g, 215.51 mmol, 1.05 eq) and K.sub.2CO.sub.3 (70.92 g, 513.12 mmol, 2.5 eq) in dioxane (200 mL) and H.sub.2O (40 mL) was added Pd(dppf)Cl.sub.2 (7.51 g, 10.26 mmol, 0.05 eq). The reaction mixture was stirred at 80 C. for 5 hours under N.sub.2 atmosphere. Then the reaction mixture was quenched by addition of H.sub.2O (600 mL) and extracted with EtOAc (2500 mL). The combined organic layers were washed with brine (2600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 100:1) to give the title compound (27 g, 77% yield, 89% purity on LCMS) as a yellow oil.

[0512] .sup.1H NMR (400 MHz, CDCl.sub.3) 6.81-6.76 (m, 2H), 6.66-6.62 (m, 1H), 5.38 (s, 1H), 5.08 (s, 1H), 3.69 (br s, 2H) and 1.25 (s, 3H).

[0513] LCMS: m/z 152.2 (M+H).sup.+ (ES.sup.+).

Step B: 4-Fluoro-2-isopropylaniline

[0514] ##STR00127##

[0515] To a solution of 4-fluoro-2-(prop-1-en-2-yl)aniline (21 g, 138.91 mmol, 1 eq) in MeOH (300 mL) was added Pd/C (2.1 g, 178.59 mmol, 10 wt % loading on activated carbon) under N.sub.2 atmosphere. The reaction mixture was degassed in vacuo and purged with H.sub.2 several times. The reaction mixture was stirred at 25 C. for 12 hours under H.sub.2 (50 psi). Then the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (20 g, crude) as a yellow oil.

[0516] .sup.1H NMR (400 MHz, CDCl.sub.3) 6.86 (dd, 1H), 6.75-6.72 (m, 1H), 6.63-6.61 (m, 1H), 3.50 (br s, 2H), 2.95-2.84 (m, 1H) and 1.25 (d, 6H).

[0517] LCMS: m/z 154.2 (M+H).sup.+ (ES.sup.+).

Step C: 2-Bromo-4-fluoro-6-isopropylaniline

[0518] ##STR00128##

[0519] To a solution of 4-fluoro-2-isopropylaniline (20 g, 130.55 mmol, 1 eq) in toluene (250 mL) was added NBS (23.24 g, 130.55 mmol, 1 eq) at 25 C. The reaction mixture was stirred at 25 C. for 10 minutes, and then poured into H.sub.2O (300 mL) and extracted with EtOAc (2250 mL). The combined organic layers were washed with brine (2400 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, only eluting with petroleum ether) to give the title compound (30 g, 99%) as a black brown oil.

[0520] .sup.1H NMR (400 MHz, CDCl.sub.3) 6.99 (dd, 1H), 6.78 (dd, 1H), 3.91 (br s, 2H), 2.88-2.71 (m, 1H) and 1.17 (d, 6H).

[0521] LCMS: m/z 232.1 (M+H).sup.+ (ES.sup.+).

Step D: 4-Fluoro-2-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0522] ##STR00129##

[0523] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (15 g, 64.63 mmol, 1 eq) and 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (18.87 g, 74.32 mmol, 1.15 eq) in dioxane (150 mL) was added AcOK (19.03 g, 193.89 mmol, 3 eq) and Pd(dppf)Cl.sub.2 (2.36 g, 3.23 mmol, 0.05 eq). The reaction mixture was stirred at 90 C. for 6 hours under N.sub.2 atmosphere. Then the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, only eluting petroleum ether) to give the title compound (14 g, 73% yield, 93.7% purity on LCMS) as a yellow oil.

[0524] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.19 (dd, 1H), 6.94 (dd, 1H), 4.71 (s, 2H), 2.90-2.82 (m, 1H), 1.35 (s, 12H) and 1.26 (d, 6H).

Step E: 4-(2-Amino-5-fluoro-3-isopropylphenyl)picolinonitrile

[0525] ##STR00130##

[0526] To a mixture of 4-fluoro-2-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (8.06 g, 27.05 mmol, 1.1 eq) and 4-bromopicolinonitrile (4.5 g, 24.59 mmol, 1 eq) in dioxane (120 mL) and H.sub.2O (25 mL) was added Na.sub.2CO.sub.3 (6.52 g, 61.47 mmol, 2.5 eq) and Pd(dppf)Cl.sub.2 (1.08 g, 1.48 mmol, 0.06 eq). The reaction mixture was stirred at 80 C. for 2 hours under N.sub.2 atmosphere. Then the reaction mixture was quenched with H.sub.2O (120 mL) and extracted with EtOAc (2150 mL). The combined organic layers were washed with brine (2200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 5:1) to give the title compound (5 g, 67% yield, 84.3% purity on LCMS) as a black brown solid.

[0527] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.78 (d, 1H), 7.86 (s, 1H), 7.64 (dd, 1H), 6.99 (dd, 1H), 6.69 (dd, 1H), 3.62 (s, 2H), 2.94-2.88 (m, 1H) and 1.29 (d, 6H).

[0528] LCMS: m/z 256.1 (M+H).sup.+ (ES.sup.+).

Step F: 4-(2-Bromo-5-fluoro-3-isopropylphenyl)picolinonitrile

[0529] ##STR00131##

[0530] To a mixture of 4-(2-amino-5-fluoro-3-isopropylphenyl)picolinonitrile (6 g, 23.50 mmol, 1 eq) in MeCN (120 mL) was added a solution of HBr (12 mL, 33% purity in AcOH solution) in H.sub.2O (12 mL). Then a solution of NaNO.sub.2 (1.95 g, 28.20 mmol, 1.2 eq) in H.sub.2O (12 mL) was added at 0 C. The resulting mixture was stirred at 0 C. for 40 minutes. Then CuBr (3.71 g, 25.85 mmol, 1.1 eq) was added. The reaction mixture was stirred at 25 C. for 1 hour, and then quenched with H.sub.2O (100 mL) and extracted with EtOAc (2150 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 40:1 to 30:1) to give the title compound (6 g, 80% yield, 99.9% purity on LCMS) as a yellow solid.

[0531] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.79 (dd, 1H), 7.73 (d, 1H), 7.53 (dd, 1H), 7.13 (dd, 1H), 6.85 (dd, 1H), 3.51-3.47 (m, 1H) and 1.29 (d, 6H).

[0532] LCMS: m/z 318.9 (M+H).sup.+ (ES.sup.+).

Step G: tert-Butyl 2-(2-(2-carbamoylpyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetate

[0533] ##STR00132##

[0534] To a mixture of 4-(2-bromo-5-fluoro-3-isopropylphenyl)picolinonitrile (1 g, 3.13 mmol, 1 eq), Pd.sub.2(dba).sub.3 (143 mg, 156.66 mol, 0.05 eq) and Xphos (149 mg, 313.31 mol, 0.1 eq) was added a solution of (2-(tert-butoxy)-2-oxoethyl) zinc (II) bromide (Intermediate A1, Step E) (0.5 M, in THF solution, 31 mL, 5 eq) at 20 C. under N.sub.2 atmosphere. The reaction mixture was stirred at 70 C. for 12 hours, and then quenched with a 1M aqueous HCl solution (20 mL) and extracted with EtOAc (320 mL). The combined organic layers were washed with brine (230 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) to give the title compound (130 mg, 7% yield, 63.7% purity on LCMS) as a yellow oil.

[0535] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.6 (d, 1H), 8.18 (d, 1H), 7.88 (s, 1H), 7.63 (dd, 1H), 7.08 (dd, 1H), 6.78 (dd, 1H), 5.62 (s, 1H), 3.44 (s, 2H), 3.13-3.07 (m, 1H), 1.42 (s, 9H) and 1.26 (d, 6H).

[0536] LCMS: m/z 373.1 (M+H).sup.+ (ES.sup.+).

Step H: tert-Butyl 2-(2-(2-cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetate

[0537] ##STR00133##

[0538] To a mixture of tert-butyl 2-(2-(2-carbamoylpyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetate (130 mg, 222.35 mol, 1 eq) in DCM (1 mL) was added TFAA (93 mg, 444.70 mol, 2 eq) and TEA (101 mg, 1.00 mmol, 4.5 eq) at 0 C. The reaction mixture was stirred at 25 C. for 2 hours, and then quenched with water (2 mL) and extracted with DCM (22 mL). The combined organic layers were washed with brine (22 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 70:1 to 50:1) to give the title compound (78 mg, 99%) as a white solid.

[0539] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.75 (d, 1H), 7.71 (d, 1H), 7.50 (dd, 1H), 7.13 (dd, 1H), 6.75 (dd, 1H), 3.40 (s, 2H), 3.14-3.07 (m, 1H), 1.44 (s, 9H) and 1.26 (d, 6H).

[0540] LCMS: m/z 355.1 (M+H).sup.+ (ES.sup.+).

Step I: 2-(2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid

[0541] ##STR00134##

[0542] To a solution of tert-butyl 2-(2-(2-cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetate (30 mg, 84.65 mol, 1 eq) in DCM (1.8 mL) was added TFA (1.8 mL). The reaction mixture was stirred at 25 C. for 1.5 hours, and then quenched with a saturated aqueous NaHCO.sub.3 solution (2 mL) and extracted with DCM (21 mL). The combined organic layers were washed with brine (22 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (27 mg, crude) as a yellow oil, which was used directly in the following step.

[0543] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.55 (d, 1H), 7.70 (d, 1H), 7.50 (dd, 1H), 7.13 (dd, 1H), 6.75 (dd, 1H), 3.51 (s, 2H), 3.14-3.07 (m, 1H) and 1.25 (d, 6H).

[0544] LCMS: m/z 299.1 (M+H).sup.+ (ES.sup.+).

Intermediate A8: 2-(5-(2-Carbamoylpyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid

Step A: 4-Nitro-2,3-dihydro-1H-indene

[0545] ##STR00135##

[0546] To a mixture of 2,3-dihydro-1H-indene (60 g, 507.72 mmol, 1 eq) in concentrated H.sub.2SO.sub.4 (30 mL) was added a solution of HNO.sub.3 (50 mL, 69 wt % in aqueous solution) in concentrated H.sub.2SO.sub.4 (50 mL, 98 wt % in aqueous solution) dropwise at 0 C. over a period of 3.5 hours. The reaction mixture was stirred at 0 C. for 0.5 hour, and then poured into ice water (600 mL) and extracted with ethyl acetate (2400 mL). The combined organic layers were washed with water (500 mL), saturated aqueous NaHCO.sub.3 solution (500 mL) and brine (2500 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 100:1) to give the title compound (55 g, contained another regio-isomer) as a colourless oil.

[0547] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.98 (d, 1H), 7.51 (d, 1H), 7.30 (t, 1H), 3.41 (t, 2H), 302 (t, 2H) and 2.22-2.20 (m, 2H).

Step B: 2,3-Dihydro-1H-inden-4-amine

[0548] ##STR00136##

[0549] To a solution of 4-nitro-2,3-dihydro-1H-indene (55 g, contained another regio-isomer) in MeOH (500 mL) was added Pd/C (5 g, 10 wt % loading on activated carbon) under N.sub.2. The suspension was degassed in vacuo and purged with H.sub.2 several times. The reaction mixture was stirred under H.sub.2 (50 psi) at 20 C. for 12 hours. Then the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 100:4) to give the title compound (19.82 g, 43% yield, 96.4% purity on LCMS) as a brown oil.

[0550] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.01 (t, 1H), 6.71 (d, 1H), 6.51 (d, 1H), 3.57 (br s, 2H), 2.93 (t, 2H), 2.75 (t, 2H) and 2.16-2.08 (m, 2H).

[0551] LCMS: m/z 134.2 (M+H).sup.+ (ES.sup.+).

Step C: N-(2,3-Dihydro-1H-inden-4-yl)acetamide

[0552] ##STR00137##

[0553] To a solution of 2,3-dihydro-1H-inden-4-amine (19.8 g, 148.66 mmol, 1 eq) and TEA (19.56 g, 193.26 mmol, 1.3 eq) in DCM (300 mL) was added dropwise Ac.sub.2O (17.45 g, 170.96 mmol, 1.15 eq) over 0.1 hour at 0 C. Then the reaction mixture was warmed to 16 C. and stirred for 1.4 hours. The reaction mixture was poured into water (500 mL) and extracted with DCM (2300 mL). The combined organic layers were washed with brine (2500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (25.74 g, 96% yield, 96.7% purity on LCMS) as a white solid.

[0554] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.70 (d, 1H), 7.15 (t, 1H), 7.02 (d, 1H), 2.95 (t, 2H), 2.81 (t, 2H), 2.18 (s, 3H) and 2.15-2.08 (m, 2H).

[0555] LCMS: m/z 176.2 (M+H).sup.+ (ES.sup.+).

Step D: N-(5-Bromo-2,3-dihydro-1H-inden-4-yl)acetamide

[0556] ##STR00138##

[0557] A mixture of N-(2,3-dihydro-1H-inden-4-yl)acetamide (34.6 g, 197.46 mmol, 1 eq), 4-methylbenzenesulfonic acid (18.70 g, 108.60 mmol, 0.55 eq) and Pd(OAc).sub.2 (2.22 g, 9.87 mmol, 0.05 eq) were suspended in toluene (400 mL) and then stirred at 20 C. for 0.5 hour under air atmosphere. NBS (38.66 g, 217.20 mmol, 1.1 eq) was added. The resulting reaction mixture was stirred at 20 C. for 2 hours, and then poured into water (500 mL) and extracted with ethyl acetate (2500 mL). The combined organic layers were washed with brine (2500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 2:1) to give the title compound (13.9 g, 27% yield, 98.1% purity on LCMS) as a white solid.

[0558] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.33 (d, 1H), 7.16 (s, 1H), 6.98 (d, 1H), 2.92-2.83 (m, 4H), 2.21 (s, 3H) and 2.10-2.02 (m, 2H).

[0559] LCMS: m/z 254.1 (M+H).sup.+ (ES.sup.+).

Step E: 5-Bromo-2,3-dihydro-1H-inden-4-amine

[0560] ##STR00139##

[0561] A mixture of N-(5-bromo-2,3-dihydro-1H-inden-4-yl)acetamide (45.68 g, 179.76 mmol, 1 eq) in EtOH (200 mL) and concentrated HCl (300 mL, 36 wt % in aqueous solution) was stirred at 80 C. for 36 hours. Then the reaction mixture was cooled to 0 C. in an ice bath and some solid precipitated out. The suspension was filtered. The filter cake was washed with ice water (50 mL) and dried in vacuo to give the title compound (34.1 g, 72% yield, 94.1% purity on LCMS, HCl salt) as a grey solid.

[0562] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.67 (br s, 2H), 7.24 (d, 1H), 6.69 (d, 1H), 2.85 (t, 2H), 2.79 (t, 2H) and 2.04-1.96 (m, 2H).

[0563] LCMS: m/z 212.0 (M+H).sup.+ (ES.sup.+).

Step F: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-4-amine

[0564] ##STR00140##

[0565] To a solution of 5-bromo-2,3-dihydro-1H-inden-4-amine (15 g, 70.73 mmol, 1 eq) and 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (19.76 g, 77.80 mmol, 1.1 eq) in dioxane (150 mL) was added KOAc (20.82 g, 212.18 mmol, 3 eq) and Pd(dppf)Cl.sub.2 (2.59 g, 3.54 mmol, 0.05 eq). The reaction mixture was stirred at 100 C. for 12 hours under nitrogen, and then diluted with water (300 mL) and extracted with ethyl acetate (3300 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 100:1 to 50:1) to give the title compound (14 g, 76%) as a yellow solid.

[0566] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.48 (d, 1H), 6.66 (d, 1H), 4.70 (br s, 2H), 2.92 (t, 2H), 2.71 (t, 2H), 2.15-2.09 (m, 2H) and 1.36 (s, 12H).

[0567] LCMS: m/z 260.2 (M+H).sup.+ (ES.sup.+).

Step G: 4-(4-Amino-2,3-dihydro-1H-inden-5-yl)picolinonitrile

[0568] ##STR00141##

[0569] To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-4-amine (14 g, 54.02 mmol, 1 eq) and 4-bromopicolinonitrile (7.91 g, 43.22 mmol, 0.8 eq) in dioxane (140 mL) and H.sub.2O (14 mL) was added Na.sub.2CO.sub.3 (14.31 g, 135.06 mmol, 2.5 eq) and Pd(dppf)Cl.sub.2 (1.98 g, 2.70 mmol, 0.05 eq). The reaction mixture was stirred at 100 C. for 3 hours, and then diluted with water (300 mL) and extracted with ethyl acetate (3300 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 2:1) to give the title compound (11 g, 87%) as a white solid.

[0570] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.65 (d, 1H), 7.79 (d, 1H), 7.59 (dd, 1H), 6.87 (d, 1H), 6.73 (d, 1H), 3.64 (s, 2H), 2.90 (t, 2H), 2.70 (t, 2H) and 2.14-2.09 (m, 2H).

[0571] LCMS: m/z 235.9 (M+H).sup.+ (ES.sup.+).

Step H: 4-(4-Bromo-2,3-dihydro-1H-inden-5-yl)picolinonitrile

[0572] ##STR00142##

[0573] To a mixture of 4-(4-amino-2,3-dihydro-1H-inden-5-yl)picolinonitrile (3 g, 12.75 mmol, 1 eq) in MeCN (60 mL) was added HCl (6 mL, 36 wt % aqueous solution) in H.sub.2O (6 mL) at 0 C. Then a solution of NaNO.sub.2 (1.06 g, 15.30 mmol, 1.2 eq) in H.sub.2O (6 mL) was added at 0 C. After addition, the reaction mixture was stirred at 0 C. for 30 minutes.

[0574] Then CuBr (2.01 g, 14.03 mmol, 1.1 eq) was added and the resulting mixture was stirred at 25 C. for 1 hour. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (350 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 5:1) to give the title compound (2.3 g, 59% yield, 98% purity on LCMS) as a white solid.

[0575] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.76-8.74 (m, 1H), 7.80 (dd, 1H), 7.62-7.60 (m, 1H), 7.25-7.23 (m, 1H), 7.12-7.09 (m, 1H), 3.14-3.02 (m, 4H), and 2.21-2.15 (m, 2H).

[0576] LCMS: m/z 298.9 (M+H).sup.+ (ES.sup.+).

Step I: (2-Ethoxy-2-oxoethyl) zinc (II) bromide

[0577] ##STR00143##

[0578] A mixture of zinc (25.45 g, 389.22 mmol, 5 eq) in aqueous HCl solution (1 M, 77.84 mL, 1 eq) was stirred at 25 C. for 30 minutes. The mixture was filtered and the filter cake was dried in vacuo. To a mixture of the above Zn and TMSCl (846 mg, 7.78 mmol, 0.1 eq) in THF (150 mL) was added ethyl 2-bromoacetate (13 g, 77.84 mmol, 1 eq) slowly at 45 C. Then the reaction mixture was cooled to 25 C. and stirred for another 1.5 hours. The resulting yellow mixture (0.5 M, in THF, 150 mL) was used directly in the next step.

Step J: Ethyl 2-(5-(2-carbamoylpyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetate

[0579] ##STR00144##

[0580] To a mixture of 4-(4-bromo-2,3-dihydro-1H-inden-5-yl)picolinonitrile (3.7 g, 12.37 mmol, 1 eq) in THF (10 mL) was added Xphos (589 mg, 1.24 mmol, 0.1 eq), Pd.sub.2(dba).sub.3 (566 mg, 618.39 mol, 0.05 eq) and (2-ethoxy-2-oxoethyl) zinc (II) bromide (0.5 M, 98.94 mL, 4 eq). The reaction mixture was stirred at 70 C. for 12 hours, and then quenched with 1N aqueous HCl solution (10 mL) and extracted with ethyl acetate (330 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) to give the title compound (1 g, 24% yield, 95% purity on LCMS) as a yellow solid.

[0581] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.96 (s, 1H), 8.57 (s, 1H), 8.38 (br s, 1H), 7.88 (d, 1H), 7.30-7.28 (m, 1H), 7.17 (d, 1H), 4.17 (q, 2H), 3.56 (s, 2H), 3.00 (t, 2H), 2.95 (t, 2H), 2.18-2.09 (m, 2H) and 1.27 (t, 3H).

[0582] LCMS: m/z 325.0 (M+H).sup.+ (ES.sup.+).

Step K: 2-(5-(2-Carbamoylpyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid

[0583] ##STR00145##

[0584] To a mixture of ethyl 2-(5-(2-carbamoylpyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetate (400 mg, 1.23 mmol, 1 eq) in THF (1 mL) was added NaH (59 mg, 1.48 mmol, 60 wt % in mineral oil, 1.2 eq) at 0 C. The reaction mixture was stirred at 25 C. for 12 hours, and then quenched with EtOH (5 mL), filtered and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% TFA in water-MeCN) to give the title compound (200 mg, 47% yield, 86% purity on LCMS) as a yellow solid.

[0585] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.68 (d, 1H), 8.18 (s, 1H), 7.95 (d, 1H), 7.70 (s, 1H), 7.51 (dd, 1H), 7.27 (d, 1H), 7.09 (d, 1H), 3.48 (s, 2H), 2.95 (t, 2H), 2.85 (t, 2H) and 2.11-2.03 (m, 2H).

[0586] LCMS: m/z 297.1 (M+H).sup.+ (ES.sup.+).

Intermediate A9: 2-Acetoxy-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid

Step A: Ethyl 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate

[0587] ##STR00146##

[0588] To a mixture of 4-(2-bromo-5-fluoro-3-isopropylphenyl)-2-methoxypyridine (Intermediate A1, Step D) (11 g, 33.93 mmol, 1 eq), Pd.sub.2(dba).sub.3 (1.55 g, 1.70 mmol, 0.05 eq) and Xphos (1.62 g, 3.39 mmol, 0.1 eq) in THF (20 mL) was added (2-ethoxy-2-oxoethyl) zinc (II) bromide (Intermediate A8, Step I) (0.5 M, 135.72 mL, 2 eq) at 20 C. under N. The mixture was stirred at 70 C. for 5 hours under N.sub.2, and then concentrated in vacuo. The residue was poured into water (30 mL) and extracted with ethyl acetate (230 mL). The combined organic layers were washed with brine (250 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 100:1) to give the title compound (10.8 g, 95% yield, 99% purity on LCMS) as a red oil.

[0589] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.19-8.17 (m, 1H), 7.07 (d, 1H), 6.83-6.80 (m, 1H), 6.79-6.76 (m, 1H), 6.68 (d, 1H), 4.11 (q, 2H), 3.97 (s, 3H), 3.51 (s, 2H), 3.09-3.03 (m, 1H) and 1.27-1.21 (m, 9H).

[0590] LCMS: m/z 332.0 (M+H).sup.+ (ES.sup.+).

Step B: Ethyl 2-bromo-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate

[0591] ##STR00147##

[0592] To a mixture of ethyl 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate (2 g, 6.04 mmol, 1 eq) in THF (20 mL) was added NaHMDS (1 M, 12.07 mL, 2 eq) at 0 C. The reaction mixture was stirred at 20 C. for 1 hour. Then NBS (1.61 g, 9.05 mmol, 1.5 eq) was added. The resulting mixture was stirred at 20 C. for 12 hours, and then quenched with water (30 mL) and extracted with EtOAc (330 mL). The combined organic layers were concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1) and then further purified by prep-HPLC (column: Xbridge BEH C18, 250 mm*50 mm*10 m; mobile phase [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 55%-80%, 16 min) to give the title compound (430 mg, 17%) as a yellow oil.

[0593] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.28-8.24 (m, 1H), 7.07 (dd, 1H), 6.90 (s, 1H), 6.76 (s, 1H), 6.74 (dd, 1H), 5.63 (s, 1H), 4.28-4.25 (m, 1H), 4.15-4.12 (m, 1H), 4.00 (s, 3H), 3.24-3.21 (m, 1H) and 1.35-1.19 (m, 9H).

[0594] LCMS: m/z 410.0 (M+H).sup.+ (ES.sup.+).

Step C: Ethyl 2-acetoxy-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate

[0595] ##STR00148##

[0596] To a mixture of ethyl 2-bromo-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate (430 mg, 807.02 mol, 1 eq) in DMF (5 mL) was added AcOK (396 mg, 4.04 mmol, 5 eq). The reaction mixture was stirred at 80 C. for 12 hours, and then diluted with water (15 mL) and extracted with EtOAc (315 mL). The combined organic layers were concentrated in vacuo. The residue was purified by prep-TLC (petroleum ether:ethyl acetate, 10:1) to give the title compound (280 mg, 86% yield, 97% purity on LCMS) as a yellow gum.

[0597] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.12 (d, 1H), 7.02 (dd, 1H), 6.71 (s, 1H), 6.69 (dd, 1H), 6.67 (s, 1H), 6.24 (s, 1H), 4.16-4.01 (m, 2H), 3.91 (s, 3H), 3.24-3.21 (m, 1H), 2.04 (s, 3H), 1.22 (d, 3H), 1.15 (t, 3H) and 1.08 (d, 3H).

[0598] LCMS: m/z 390.1 (M+H).sup.+ (ES.sup.+).

Step D: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-2-hydroxyacetic acid

[0599] ##STR00149##

[0600] To a mixture of ethyl 2-acetoxy-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate (150 mg, 385.19 mol, 1 eq) in EtOH (1 mL) and H.sub.2O (1 mL) was added LiOH.H.sub.2O (48 mg, 1.16 mmol, 3 eq). The reaction mixture was stirred at 20 C. for 5 hours, and then concentrated to remove EtOH. The residue was adjusted to pH 56 with 1N aqueous HCl solution and then the mixture was extracted with EtOAc (315 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (110 mg, 85% yield, 95% purity on LCMS) as a colourless gum, which was used in the next step without further purification.

[0601] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.18 (d, 1H), 7.11 (dd, 1H), 6.95 (d, 1H), 6.82-6.78 (m, 2H), 5.30 (s, 1H), 3.96 (s, 3H), 3.23-3.20 (m, 1H) and 1.30-1.20 (m, 6H).

[0602] LCMS: m/z 320.0 (M+H).sup.+ (ES.sup.+).

Step E: 2-Acetoxy-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid

[0603] ##STR00150##

[0604] To a mixture of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-2-hydroxyacetic acid (95 mg, 297.50 mol, 1 eq) in DCM (1 mL) was added DMAP (4 mg, 29.75 mol, 0.1 eq) and Ac.sub.2O (91 mg, 892.50 mol, 3 eq). The reaction mixture was stirred at 20 C. for 12 hours, and then diluted with water (2 mL) and extracted with DCM (32 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (DCM:MeOH, 10:1) to give the title compound (40 mg, 36% yield, 98% purity on LCMS) as a white solid.

[0605] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.13 (d, 1H), 7.05 (dd, 1H), 6.79-6.73 (m, 3H), 6.15 (s, 1H), 3.91 (s, 3H), 3.31-3.29 (m, 1H), 1.96 (s, 3H), 1.22 (d, 3H) and 1.06 (d, 3H).

[0606] LCMS: m/z 362.0 (M+H).sup.+ (ES.sup.+).

Intermediate A10: 2-(4-Fluoro-2-(2-fluoropropan-2-vl)-6-(2-methoxypyridin-4-yl)phenyl)acetic acid

Step A: Methyl 2-amino-5-fluoro-3-iodobenzoate

[0607] ##STR00151##

[0608] To a mixture of methyl 2-amino-5-fluorobenzoate (4.9 g, 29 mmol, 1 eq) and silver sulfate (9.1 g, 29 mmol, 1 eq) in ethanol (60 mL) was added iodine (7.4 g, 29 mmol, 1 eq) at room temperature. After stirring for 1 hour under nitrogen atmosphere, the reaction mixture was quenched using a saturated solution of sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and then concentrated in vacuo. The crude product was submitted to normal phase flash chromatography using heptane and ethyl acetate as eluent to afford the title compound (7.53 g, 25.5 mmol, 87%).

[0609] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.72-7.47 (m, 2H), 6.18 (s, 2H), 3.89 (d, 3H).

Step B: Methyl 2-amino-5-fluoro-3-(2-methoxypyridin-4-yl)benzoate

[0610] ##STR00152##

[0611] A solution of methyl 2-amino-5-fluoro-3-iodobenzoate (3.1 g, 11 mmol, 1 eq) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.0 g, 13 mmol, 1.2 eq) in 1,4-dioxane (50 mL) and water (10 mL) was degassed with nitrogen. After that, potassium carbonate (4.4 g, 32 mmol, 3 eq) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.51 g, 0.06 eq, 0.63 mmol) were added. The reaction mixture was heated in a sand bath set to 80 C. After stirring for 2.5 hours, the reaction mixture was cooled to room temperature and diluted with water. The mixture was extracted with dichloromethane. The organic layer was washed with water, once with brine, dried over sodium sulfate, filtered and then concentrated in vacuo. The crude product was purified by normal phase flash chromatography using heptane and ethyl acetate as eluent to afford the title compound (2.55 g, 9.23 mmol, 88%).

[0612] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.27 (d, 1H), 7.63 (dd, 1H), 7.07-6.89 (m, 2H), 6.81 (s, 1H), 5.86 (s, 2H), 4.00 (s, 3H), 3.90 (s, 3H).

Step C: Methyl 2-bromo-5-fluoro-3-(2-methoxypyridin-4-yl)benzoate

[0613] ##STR00153##

[0614] To a solution of methyl 2-amino-5-fluoro-3-(2-methoxypyridin-4-yl)benzoate (500 mg, 1.81 mmol, 1 eq) in acetonitrile (10 mL) cooled in a brine-ice bath was added hydrobromic acid (2.0 mL, 18.1 mmol, 10 eq) followed by a solution sodium nitrite (137 mg, 1.99 mmol, 1.1 eq) in water (1.5 mL). The clear orange solution was stirred at 0 C. for 45 minutes and then copper(II) bromide (445 mg, 1.99 mmol, 1.1 eq) and copper(I) bromide (260 mg, 1.81 mmol, 1 eq) were added. The reaction mixture was continued to be stirred in the brine-ice bath while allowing the ice to melt. After 1 hour, the mixture was carefully basified with solid sodium bicarbonate (pH approximate 7) and extracted with ethyl acetate. The organic layer was washed with a saturated solution of sodium bicarbonate until the aqueous phase was not blue, then washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by normal phase flash chromatography using heptane and ethyl acetate as eluent to afford the title compound (562 mg, 1.65 mmol, 91%).

[0615] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.24 (dd, 1H), 7.40 (dd, 1H), 7.12 (dd, 1H), 6.87 (dd, 1H), 6.72 (dd, 1H), 3.99 (s, 3H), 3.97 (s, 3H).

Step D: Methyl 2-allyl-5-fluoro-3-(2-methoxypyridin-4-yl)benzoate

[0616] ##STR00154##

[0617] A solution of methyl 2-bromo-5-fluoro-3-(2-methoxypyridin-4-yl)benzoate (561 mg, 1.65 mmol, 1 eq) in 1,4-dioxane (10 mL) in a microwave vial was degassed with nitrogen. After that, 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.55 mL, 2.97 mmol, 1.8 eq), cesium fluoride (501 mg, 3.30 mmol, 2 eq) and tetrakis(triphenylphosphine)palladium(0) (191 mg, 0.16 mmol, 0.1 eq) were added. The microwave vial was capped and placed in a sand bath heated to 110 C. After stirring for 22 hours, the reaction mixture was cooled to room temperature and diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by normal phase column chromatography using heptane and ethyl acetate to afford the title compound (365 mg, 1.21 mmol, 73%).

[0618] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.19 (dd, 1H), 7.57 (dd, 1H), 7.05 (dd, 1H), 6.81 (dd, 1H), 6.67 (dd, 1H), 5.96-5.66 (m, 1H), 4.96 (dt, 1H), 4.66 (dq, 1H), 3.99 (s, 3H), 3.89 (s, 3H), 3.60 (dt, 2H).

Step E: 2-(2-Allyl-5-fluoro-3-(2-methoxypyridin-4-yl)phenyl)propan-2-ol

[0619] ##STR00155##

[0620] To a solution of methyl 2-allyl-5-fluoro-3-(2-methoxypyridin-4-yl)benzoate (365 mg, 1.21 mmol, 1 eq) in anhydrous tetrahydrofuran (12 mL) was added dropwise methyl magnesium bromide (3M solution in diethyl ether, 2 mL, 6.06 mmol, 5 eq). After stirring overnight at room temperature, the reaction mixture was quenched with a saturated solution of ammonium chloride and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and then concentrated in vacuo to afford the title compound (361 mg, 1.20 mmol, 98%), which was used as such for the following reaction.

[0621] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.15 (dd, 1H), 7.22 (dd, 1H), 6.81-6.75 (m, 2H), 6.66 (dd, 1H), 5.83 (ddt, 1H), 4.95 (dq, 1H), 4.52 (dq, 1H), 3.98 (s, 3H), 3.70 (dt, 2H), 1.66 (s, 6H).

Step F: 4-(2-Allyl-5-fluoro-3-(2-fluoropropan-2-yl)phenyl)-2-methoxypyridine

[0622] ##STR00156##

[0623] To a solution of 2-(2-allyl-5-fluoro-3-(2-methoxypyridin-4-yl)phenyl)propan-2-ol (361 mg, 1.20 mmol, 1 eq) and triethylamine trihydrofluoride (0.70 mL, 4.31 mmol, 3.6 eq) in dichloromethane (6 mL) was added XtalFluor-E (988 mg, 4.31 mmol, 3.6 eq). The reaction mixture was stirred at room temperature for 50 minutes and then quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with a saturated solution of sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and then concentrated in vacuo. The crude product was purified by normal phase column chromatography using heptane and ethyl acetate as eluent to afford the title compound (176 mg, 0.35 mmol, 29% yield, 60% purity by UPLC), which was used as such in the following reaction.

[0624] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.23-8.11 (m, 1H), 7.17-7.05 (m, 1H), 6.87-6.73 (m, 2H), 6.65 (dd, 1H), 5.82-5.62 (m, 1H), 4.94-4.84 (m, 1H), 4.50 (dd, 1H), 3.98 (d, 3H), 3.55-3.41 (m, 2H), 1.77 (d, 6H).

Step G: 2-(4-Fluoro-2-(2-fluoropropan-2-yl)-6-(2-methoxypyridin-4-yl)phenyl)acetic acid

[0625] ##STR00157##

[0626] To a mixture of 4-(2-allyl-5-fluoro-3-(2-fluoropropan-2-yl)phenyl)-2-methoxypyridine (176 mg, 60% purity, 0.35 mmol, 1 eq) in ethyl acetate (3 mL), water (5 mL) and acetonitrile (3 mL) were added ruthenium(III) chloride hydrate (2.6 mg, 11.6 mol, 0.03 eq) and sodium periodate (248 mg, 1.16 mmol, 3.3 eq). After stirring for 4 hours at room temperature, more ruthenium(III) chloride hydrate (4.0 mg, 18 mol, 0.05 eq) and sodium periodate (248 mg, 1.16 mmol, 3.3 eq) were added. After stirring over the weekend, more ruthenium(III) chloride hydrate (17 mg, 75 mol, 0.22 eq) and sodium periodate (248 mg, 1.16 mmol, 3.3 eq) were added. After stirring for 2 further hours, the reaction mixture was filtered over a pad of Celite. The residue was washed extensively with ethyl acetate. The filtrates were combined and washed with water, washed once with brine, dried over sodium sulfate, filtered and then concentrated in vacuo. The crude product was purified by normal phase flash chromatography using heptane and ethyl acetate as eluent to afford the title compound (38 mg, 0.12 mmol, 34%).

[0627] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.19 (d, 1H), 7.10-6.98 (m, 1H), 6.92-6.76 (m, 2H), 6.68 (d, 1H), 3.97 (s, 3H), 3.75 (d, 2H), 1.77 (d, 6H).

Intermediate A11: 2-(4-Fluoro-2-isopropyl-6-(6-methoxypyridin-3-yl)phenyl)acetic acid, TFA salt

Step A: 4-Fluoro-2-isopropyl-6-(6-methoxypyridin-3-yl)aniline

[0628] ##STR00158##

[0629] Potassium carbonate (2.2 g, 16 mmol) was dissolved in water (5 mL) and added to a solution of 5-bromo-2-methoxypyridine (1.1 g, 5.6 mmol) and 4-fluoro-2-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Intermediate A7, Step D) (1.5 g, 5.4 mmol) in dioxane (30 mL). The mixture was brought under N.sub.2 atmosphere and Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (0.22 g, 0.27 mmol) was added, after which the mixture was refluxed for 2 hours. Water (40 mL) was added and the mixture was extracted with ethyl acetate (275 mL), dried over sodium sulfate, and evaporated to dryness yielding the title compound (1.9 g, 93%) as a brown oil.

[0630] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.21 (d, 1H), 7.64 (dd, 1H), 6.91 (dd, 1H), 6.82 (d, 1H), 6.68 (dd, 1H), 3.99 (s, 3H), 2.90-2.82 (m, 1H), 2.00 (bs, 2H) and 1.26 (d, 6H).

[0631] LCMS: m/z 261 (M+H).sup.+ (ES.sup.+).

Step B: 5-(2-Bromo-5-fluoro-3-isopropylphenyl)-2-methoxypyridine

[0632] ##STR00159##

[0633] 4-Fluoro-2-isopropyl-6-(6-methoxypyridin-3-yl)aniline (0.85 g, 1 eq, 3.3 mmol) in acetonitrile (100 mL) at 0 C. was treated with concentrated HBr (5.5 g) in water (7 mL). Sodium nitrite (0.25 g, 1.1 eq, 3.6 mmol) in water (10 mL) was added and the mixture was stirred at 0 C. for 45 minutes. Copper(I) bromide (0.47 g, 1 eq, 3.3 mmol) and copper(II) bromide (0.73 g, 1 eq, 3.3 mmol) were added and the mixture was allowed to reach room temperature over 2 hours. Sodium carbonate (1.0 g, 2.9 eq, 9.4 mmol) and water (80 mL) were added and the mixture was stirred for 10 minutes. The layers were separated and the water layer was extracted with ethyl acetate (30 mL). The combined organic layers were evaporated and the residue was resuspended in DCM (so mL). The suspension was washed with concentrated ammonia (215 mL), dried over sodium sulfate and evaporated to dryness, yielding the title compound (0.4 g, 40%) as a brown oil.

[0634] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.21 (d, 1H), 7.02 (dd, 1H), 6.91 (dd, 1H), 6.82 (d, 1H), 6.68 (dd, 1H), 4.02 (s, 3H), 3.22 (m, 1H) and 1.26 (d, 6H).

[0635] LCMS: m/z 324 (M+H).sup.+ (ES.sup.+).

Step C: 4-Fluoro-2-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0636] ##STR00160##

[0637] 5-(2-Bromo-5-fluoro-3-isopropylphenyl)-2-methoxypyridine (0.60 g, 1 eq, 1.9 mmol) was dissolved in THF (8 mL) and brought under N.sub.2 atmosphere. Pd.sub.2(dba).sub.3 chloroform adduct (96 mg, 0.05 eq, 93 mol) and Xphos (88 mg, 0.1 eq, 0.19 mmol) were added, followed by (2-(tert-butoxy)-2-oxoethyl) zinc (II) bromide (Intermediate A1, Step E) (1.1 g, 2.2 eq, 4.1 mmol) in THF. The mixture was stirred at 80 C. overnight. The mixture was filtered over Celite, evaporated to near dryness and subjected to column chromatography (SiO.sub.2, heptanes, gradient to 20% ethyl acetate) yielding the title compound (0.08 g, 12%) as a clear oil.

[0638] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.09 (d, 1H), 7.56 (dd, 1H), 7.02 (dd, 1H), 6.78 (m, 2H), 3.99 (s, 3H), 3.45 (s, 2H), 3.07 (m, 1H), 1.40 (s, 9H) and 1.26 (d, 6H).

[0639] LCMS: m/z 304 (MtBu+2H).sup.+ (ES.sup.+).

Step D: 2-(4-Fluoro-2-isopropyl-6-(6-methoxypyridin-3-yl)phenyl)acetic acid, TFA

[0640] ##STR00161##

[0641] tert-Butyl 2-(4-fluoro-2-isopropyl-6-(6-methoxypyridin-3-yl)phenyl)acetate (0.08 g, 0.22 mmol) was dissolved in DCM (5 mL) and TFA (1 mL). The mixture was stirred at room temperature for 3 hours and evaporated to dryness by rotary evaporation, yielding the title compound (0.10 g, 85%) as a clear oil.

[0642] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.24 (d, 1H), 7.86 (dd, 1H), 7.12 (dd, 1H), 7.02 (d, 1H), 6.78 (d, 1H), 4.07 (s, 3H), 3.59 (s, 2H), 3.07 (m, 1H) and 1.23 (d, 6H).

[0643] LCMS: m/z 304 (M+H).sup.+ (ES.sup.+).

Intermediate A12: 2-(4-Fluoro-2-isopropyl-6-(4-methoxypyridin-3-yl)phenyl)acetic acid

Step A: 2-(4-Fluoro-2-(prop-1-en-2-yl)phenyl)acetic acid

[0644] ##STR00162##

[0645] Potassium carbonate (120 g, 0.89 mol) was dissolved in water (100 mL) and added to a solution of 2-(2-bromo-4-fluorophenyl)acetic acid (69 g, 1 eq, 0.30 mol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (50 g, 1 eq, 0.30 mol) in 1,4-dioxane (100 mL). The mixture was brought under a N.sub.2 atmosphere and Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 adduct (4.9 g, 6.0 mmol) was added. The reaction mixture was refluxed for 48 hours, and then cooled to room temperature. Water was added until all salts were dissolved. The layers were separated and the aqueous layer was extracted with ethyl acetate (2100 mL). The combined organic layers were dried over sodium sulfate and solvent was removed by rotary evaporation, yielding the title compound (87 g, 94%) as a brown oil. The crude product was a 1:1 mixture with 2,3-dimethylbutane-2,3-diol.

[0646] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.22 (dd, 1H), 6.95 (dd, 1H), 6.88 (dd, 1H), 5.23 (s, 1H), 4.84 (s, 1H), 3.68 (s, 2H), 2.00 (s, 3H), 1.24 (s, 6H), 1.21 (s, 6H).

[0647] LCMS: m/z 193 (MH).sup. (ES.sup.).

Step B: 2-(4-Fluoro-2-isopropylphenyl)acetic acid

[0648] ##STR00163##

[0649] 2-(4-Fluoro-2-(prop-1-en-2-yl)phenyl)acetic acid mixture with 2,3-dimethylbutane-2,3-diol (1:1) (80 g, 0.26 mol) and platinum(IV) oxide (1 g, 4 mmol) were dissolved in ethanol (200 mL) and stirred overnight under H.sub.2 (3 bar). Additional platinum(IV) oxide (0.1 g, 0.4 mmol) was added, and the reaction mixture was stirred for another 5 hours under H.sub.2 (3 bar). Then the reaction mixture was filtered over Celite and ethanol was removed by rotary evaporation. The resulting oil was subjected to falling film distillation to remove the residual pinacol. The crude product was filtered over a plug of SiO.sub.2 (510 cm), and eluted with DCM (2 L). Rotary evaporation of the collected eluate yielded the title compound (45 g, 90%) as a crystalline, light orange solid.

[0650] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.18 (dd, 1H), 7.00 (dd, 1H), 6.82 (dt, 1H), 3.67 (s, 2H), 3.07 (m, 1H), 1.20 (d, 6H).

[0651] LCMS: m/z 195 (MH).sup. (ES.sup.).

Step C: 2-(4-Fluoro-2-iodo-6-isopropylphenyl)acetic acid

[0652] ##STR00164##

[0653] 2-(4-Fluoro-2-isopropylphenyl)acetic acid (1.75 g, 8.92 mmol), [bis(acetoxy)iodo]benzene (2.87 g, 8.92 mmol), iodine (1.70 g, 6.69 mmol) and palladium(II)acetate (100 mg, 446 mol) were dissolved in DMF (30 mL) and stirred overnight at 60 C. The mixture was filtered over Celite and the DMF was largely removed by rotary evaporation. The crude product was subjected to column chromatography (SiO.sub.2, gradient from 100% heptanes to 84% heptanes, 14.5% ethyl acetate and 1.5% formic acid) yielding the title compound (1.3 g, 45%) as a white solid, still containing 25% starting material, which was removed in the subsequent step.

[0654] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.48 (dd, 1H), 7.02 (dd, 1H), 4.01 (s, 2H), 3.04 (m, 1H), 1.20 (d, 6H).

[0655] LCMS: m/z 321 (MH).sup. (ES.sup.).

Step D: 2-(4-Fluoro-2-isopropyl-6-(4-methoxypyridin-3-yl)phenyl)acetic acid

[0656] ##STR00165##

[0657] Potassium carbonate (1.2 g, 8.4 mmol) was dissolved in water (5 mL) and added to a solution of 2-(4-fluoro-2-iodo-6-isopropylphenyl)acetic acid (1.0 g, 2.8 mmol) and 4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.66 g, 2.8 mmol) in 1,4-dioxane (20 mL). The mixture was brought under N.sub.2 atmosphere and Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 adduct (0.11 g, 0.05 eq, 0.14 mmol) was added. The reaction mixture was refluxed overnight, and then decanted. The supernatant was filtered and the filtrate was evaporated to near dryness by rotary evaporation. The crude product was dissolved in DMSO (2 mL) and water (0.2 mL), and subjected to reversed phase chromatography, yielding the title compound (0.46 g, 54%) as a white solid.

[0658] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.16 (d, 1H), 7.79 (dd, 1H), 7.02 (dd, 1H), 6.82 (d, 1H), 6.75 (dd, 1H), 3.92 (s, 3H), 3.40 (s, 2H), 3.21 (m, 1H), 1.22 (d, 6H).

[0659] LCMS: m/z 304 (M+H).sup.+ (ES.sup.+), m/z 302 (MH).sup. (ES.sup.).

Intermediate A13: 2-(4-Fluoro-2-isopropyl-6-(3-methylpyridin-4-yl)phenyl)acetic acid

[0660] ##STR00166##

[0661] Potassium carbonate (0.58 g, 4.2 mmol) was dissolved in water (3 mL) and added to a solution of (3-methylpyridin-4-yl)boronic acid (0.38 g, 2.8 mmol) and 2-(4-fluoro-2-iodo-6-isopropylphenyl)acetic acid (1.0 g, 1 eq, 2.8 mmol) in 1,4-dioxane (20 mL). The mixture was brought under N.sub.2 atmosphere and Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 adduct (0.11 g, 0.05 eq, 0.14 mmol) was added. The reaction mixture was refluxed overnight, and then decanted. The supernatant was filtered and the filtrate was evaporated to near dryness by rotary evaporation. The crude product was dissolved in DMSO (2 mL) and water (0.2 mL), and subjected to reversed phase chromatography, yielding the title compound (0.03 g, 4%) as a white solid.

[0662] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.42 (d, 1H), 8.38 (dd, 1H), 7.35 (dd, 1H), 7.07 (dd, 1H), 6.61 (d, 1H), 3.41 (d, 1H), 3.22 (m, 1H), 3.02 (d, 1H), 2.08 (s, 3H), 1.22 (d, 3H), 1.20 (d, 3H).

[0663] LCMS: m/z 288 (M+H).sup.+ (ES.sup.+), m/z 286 (MH).sup. (ES.sup.).

Intermediate A14: 2-Fluoro-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid

Step A: 4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)aniline

[0664] ##STR00167##

[0665] To a solution of 2-bromo-4-fluoro-6-isopropylaniline (Intermediate A7, Step C) (12 g, 51.70 mmol, 1 eq) in dioxane (240 mL) and H.sub.2O (48 mL) was added (2-methoxypyridin-4-yl)boronic acid (9.49 g, 62.04 mmol, 1.2 eq) and Na.sub.2CO.sub.3 (13.70 g, 129.26 mmol, 2.5 eq). Then the reaction mixture was purged with N.sub.2 three times. Pd(dppf)Cl.sub.2 (3.78 g, 5.17 mmol, 0.1 eq) was added under N.sub.2. The resulting mixture was heated at 80 C. for 2 hours under N.sub.2. Then the reaction mixture was diluted with H.sub.2O (800 mL) and extracted with EtOAc (2600 mL). The combined organic layers were washed with brine (2800 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 70:1 to 10:1) and then triturated with hexane (100 mL) to give the title compound (10.05 g, 72% yield, 96% purity on LCMS).

[0666] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.24 (d, 1H), 6.97 (d, 1H), 6.93 (d, 1H), 6.83 (s, 1H), 6.73-6.70 (m, 1H), 3.99 (s, 3H), 3.66 (br s, 2H), 2.97-2.89 (m, 1H) and 1.29 (dd, 6H).

[0667] LCMS: m/z 261.1 (M+H).sup.+ (ES.sup.+).

Step B: 4-(2-Bromo-5-fluoro-3-isopropylphenyl)-2-methoxypyridine

[0668] ##STR00168##

[0669] To a solution of 4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)aniline (2.02 g, 1 eq), CuBr (1.32 g, 1.2 eq) and CuBr.sub.2 (9 mg, 0.005 eq) in MeCN (20 mL) was added isopentyl nitrite (1.17 g, 1.3 eq) at 0 C. Then the reaction mixture was stirred at 60 C. for 40 minutes. The mixture was poured into H.sub.2O (40 mL) and extracted with EtOAc (340 mL). The organic layers were washed with brine (250 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 70:1) to give the title compound (1.7 g, 68%) as a red oil.

[0670] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.22 (d, 1H), 7.06 (dd, 1H), 6.88 (dd, 1H), 6.84 (d, 1H), 6.73 (d, 1H), 4.00 (s, 3H), 3.53-3.46 (m, 1H) and 1.28 (d, 6H).

[0671] LCMS: m/z 324.1 (M+H).sup.+ (ES.sup.+).

Step C: Ethyl 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate

[0672] ##STR00169##

[0673] To a mixture of 4-(2-bromo-5-fluoro-3-isopropylphenyl)-2-methoxypyridine (11 g, 33.93 mmol, 1 eq), Pd.sub.2(dba).sub.3 (1.55 g, 1.70 mmol, 0.05 eq) and Xphos (1.62 g, 3.39 mmol, 0.1 eq) in THF (20 mL) was added (2-ethoxy-2-oxoethyl) zinc (II) bromide (Intermediate A8, Step I) (0.5 M, 135.72 mL, 2 eq) at 20 C. under N.sub.2. The mixture was stirred at 70 C. for 5 hours under N.sub.2. Then the reaction mixture was concentrated in vacuo. The residue was poured into water (30 mL) and extracted with ethyl acetate (230 mL). The combined organic layers were washed with brine (250 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 100:1) to give the title compound (10.8 g, 95% yield, 99% purity on LCMS) as a red oil.

[0674] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.19-8.17 (m, 1H), 7.07 (d, 1H), 6.83-6.80 (m, 1H), 6.79-6.76 (m, 1H), 6.68 (d, 1H), 4.11 (q, 2H), 3.97 (s, 3H), 3.51 (s, 2H), 3.09-3.03 (m, 1H) and 1.27-1.21 (m, 9H).

[0675] LCMS: m/z 332.0 (M+H).sup.+ (ES.sup.+).

Step D: Ethyl 2-bromo-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate

[0676] ##STR00170##

[0677] To a mixture of ethyl 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate (2 g, 6.04 mmol, 1 eq) in THF (20 mL) was added NaHMDS (1 M, 12.07 mL, 2 eq) at 0 C. The reaction mixture was stirred at 20 C. for 1 hour, then NBS (1.61 g, 9.05 mmol, 1.5 eq) was added. The resulting mixture was stirred at 20 C. for 12 hours, and then quenched with water (30 mL) and extracted with EtOAc (330 mL). The combined organic layers were concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1) and then further purified by prep-HPLC (ammonium hydroxide condition) to give the title compound (430 mg, 17%) as a yellow oil.

[0678] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.26 (dd, 1H), 7.07 (dd, 1H), 6.90 (s, 1H), 6.76 (s, 1H), 6.74 (dd, 1H), 5.63 (s, 1H), 4.28-4.25 (m, 1H), 4.15-4.12 (m, 1H), 4.00 (s, 3H), 3.24-3.20 (m, 1H) and 1.35-1.19 (m, 9H).

[0679] LCMS: m/z 410.0 (M+H).sup.+ (ES.sup.+).

Step E: Ethyl 2-acetoxy-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate

[0680] ##STR00171##

[0681] To a mixture of ethyl 2-bromo-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate (430 mg, 807.02 mol, 1 eq) in DMF (5 mL) was added AcOK (396 mg, 4.04 mmol, s eq). The reaction mixture was stirred at 80 C. for 12 hours, and then diluted with water (15 mL) and extracted with EtOAc (315 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-TLC (petroleum ether:ethyl acetate, 10:1) to give the title compound (280 mg, 86% yield, 97% purity on LCMS) as a yellow gum.

[0682] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.12 (d, 1H), 7.02 (dd, 1H), 6.71 (s, 1H), 6.69 (dd, 1H), 6.67 (s, 1H), 6.24 (s, 1H), 4.16-4.01 (m, 2H), 3.91 (s, 3H), 3.24-3.21 (m, 1H), 2.04 (s, 3H), 1.22 (d, 3H), 1.15 (t, 3H) and 1.08 (d, 3H).

[0683] LCMS: m/z 390.1 (M+H).sup.+ (ES.sup.+).

Step F: Ethyl 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-2-hydroxyacetate

[0684] ##STR00172##

[0685] To a solution of ethyl 2-acetoxy-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate (530 mg, 1.36 mmol, 1 eq) in EtOH (8 mL) was added K.sub.2CO.sub.3 (564 mg, 4.08 mmol, 3 eq). The reaction mixture was stirred at 20 C. for 1 hour, and then diluted with water (30 mL) and extracted with EtOAc (320 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 5:1) to give the title compound (220 mg, 46% yield, 99% purity on LCMS) as a colourless oil.

[0686] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.11 (d, 1H), 6.98 (dd, 1H), 6.84 (d, 1H), 6.71-6.68 (m, 2H), 5.12 (s, 1H), 4.20-4.16 (m, 1H), 4.08-4.04 (m, 1H), 3.91 (s, 3H), 3.11-3.07 (m, 1H), 1.20 (d, 3H), 1.16 (t, 3H) and 1.08 (d, 3H).

[0687] LCMS: m/z 348.0 (M+H).sup.+ (ES.sup.+).

Step G: Ethyl 2-fluoro-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate

[0688] ##STR00173##

[0689] To a solution of ethyl 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-2-hydroxyacetate (220 mg, 633.31 mol, 1 eq) in DCM (5 mL) was added DAST (204 mg, 1.27 mmol, 2 eq) at 0 C. The reaction mixture was stirred at 20 C. for 0.5 hour, and then quenched with water (10 mL) and extracted with DCM (210 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 5:1) to give the title compound (190 mg, 84% yield, 98% purity on LCMS) as a yellow oil.

[0690] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.21 (d, 1H), 7.12 (dd, 1H), 6.89 (d, 1H), 6.81 (dd, 1H), 6.77 (s, 1H), 5.84 (d, 1H), 4.28-4.12 (m, 2H), 3.99 (s, 3H), 3.27-3.24 (m, 1H), 1.29-1.23 (m, 6H) and 1.18 (d, 3H).

[0691] LCMS: m/z 350.2 (M+H).sup.+ (ES.sup.+).

Step H: 2-Fluoro-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid

[0692] ##STR00174##

[0693] To a solution of ethyl 2-fluoro-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate (190 mg, 543.83 mol, 1 eq) in EtOH (5 mL) and H.sub.2O (1 mL) was added LiOH.H.sub.2O (46 mg, 1.09 mmol, 2 eq). The reaction mixture was stirred at 20 C. for 1 hour, and then concentrated to remove EtOH. The residue was diluted with water (15 mL) and washed with EtOAc (5 mL). The aqueous layer was adjusted to pH 56 with 1N HCl and extracted with EtOAc (210 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (155 mg, crude) as a white solid, which was used in the next step without further purification.

[0694] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.22 (d, 1H), 7.14 (dd, 1H), 6.93 (d, 1H), 6.85-6.80 (m, 2H), 5.91 (d, 1H), 3.98 (s, 3H), 3.32-3.29 (m, 1H), 1.26 (d, 3H) and 1.22 (d, 3H).

[0695] LCMS: m/z 322.0 (M+H).sup.+ (ES.sup.+).

Intermediate P1: 1-Methyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

Step A: N,N-bis(4-Methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide

[0696] ##STR00175##

[0697] bis(4-Methoxybenzyl)amine (366 mg, 1.42 mmol) was dissolved in THF (20 mL) and triethylamine (261 mg, 2.58 mmol). Next, 6-oxo-1,6-dihydropyridine-3-sulfonyl chloride (250 mg, 1.29 mmol) was added portionwise. The reaction was stirred for 18 hours at room temperature. The solids were filtered off and the THF was evaporated. The residue was purified over silica using ethyl acetate as the eluent to afford the title compound (360 mg, 67%) as a pale yellow solid.

[0698] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.84 (s, 1H), 7.57 (d, 1H), 7.09 (d, 4H), 6.84 (d, 4H), 6.56 (d, 1H), 4.27 (s, 4H) 3.79 (s, 6H).

Step B: N,N-bis(4-Methoxybenzyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

[0699] ##STR00176##

[0700] N,N-bis(4-Methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (100 mg, 0.24 mmol) in THF (20 mL) was cooled to 45 C. A solution of lithium bis(trimethylsilyl)amide in THF/ethylbenzene (0.3 mL, 1M), was added dropwise. During 20 minutes stirring, the temperature was allowed to rise from 45 to 10 C., and methyl iodide (230 mg. 1.62 mmol) was added. The reaction was stirred for 2 days at room temperature. The mixture was poured into saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified over silica using ethyl acetate as the eluent to afford the title compound (30 mg, 29%) as an oil.

[0701] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.66 (d, 1H), 7.45 (dd, 1H), 7.10 (d, 4H), 6.82 (d, 4H), 6.53 (d, 1H), 4.29 (s, 4H) 3.80 (s, 6H), 3.45 (s, 3H).

[0702] LCMS: m/z 429.3 (M+H).sup.+ (ES.sup.+).

Step C: 1-Methyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

[0703] ##STR00177##

[0704] N,N-bis(4-Methoxybenzyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (30 mg, 0.07 mmol) was dissolved in TFA (5 ml). The reaction mixture was stirred for 2 days at room temperature. The TFA was evaporated and the residue was triturated in water. The aqueous layer was lyophilized to afford the title compound (13 mg, 98%) as a white solid.

[0705] .sup.1H NMR (300 MHz, D.sub.2O) 8.22 (d, 1H), 7.77 (dd, 1H), 6.58 (d, 1H), 3.48 (s, 3H).

Intermediate P2: 1-Isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

Step A: 1-Isopropyl-N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide

[0706] ##STR00178##

[0707] To N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P1, step A) (158.0 mg, 0.38 mmol) in dry DMF (1 ml) and 1,2-dimethoxyethane (4 ml), was added lithium bromide (66.21 mg, 0.76 mmol). The reaction mixture was cooled to 0 C. Sodium hydride (17 mg, 0.42 mmol) was added and the reaction mixture was stirred for 10 minutes 0 C. After 10 minutes stirring at room temperature, 2-iodopropane (234 mg, 1.38 mmol) was added. The reaction mixture was warmed at 100 C. for 36 hours. Then the reaction mixture was poured into saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified over silica using ethyl acetate as the eluent to afford the title compound (27 mg, 16%) as an oil.

[0708] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.91 (d, 1H), 7.43 (d, 1H), 7.08 (d, 4H), 6.83 (d, 4H), 6.56 (d, 1H), 5.19 (m, 1H), 4.27 (s, 4H) 3.79 (s, 6H), 1.35 (d, 6H).

[0709] LCMS: m/z 457.4 (M+H).sup.+ (ES.sup.+).

Step B: 1-Isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide

[0710] ##STR00179##

[0711] 1-Isopropyl-N,N-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (27, 0.06 mmol) was dissolved in TFA (5 ml). The reaction mixture was stirred for 20 hours at room temperature. The TFA was evaporated and the residue was triturated in water. The aqueous layer was lyophilized to afford the title compound (12 mg, 94%) as a white solid.

[0712] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.21 (d, 1H), 7.79 (dd, 1H), 6.60 (d, 1H), 5.14 (m, 1H), 1.41 (d, 6H).

Intermediate P3: 4-(2-Hydroxypropan-2-yl)-2-methylbenzenesulfonamide

[0713] ##STR00180##

[0714] Methyl 3-methyl-4-sulfamoylbenzoate (486 mg, 2.12 mmol) was stirred in THF (20 mL) and a solution of methyl magnesium bromide in diethyl ether (3M, 4 mL, 12 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 days, poured in saturated NaHCO.sub.3 (aqueous, 20 mL), concentrated partially (THF removal) and filtered. Ethyl acetate (20 mL) was used to wash the residual solid and extract the filtrate. The organic phase was separated, dried (Na.sub.2SO.sub.4), filtered and concentrated to afford the title compound (0.48 g, 99%) as a yellow solid.

[0715] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 7.89 (d, 1H), 7.47 (s, 1H), 7.45-7.39 (d, 1H), 2.66 (s, 3H), 1.52 (s, 6H).

Intermediate P4: 1-Cyclopropyl-1H-imidazole-4-sulfonamide

Step A: 4-Iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and 5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

[0716] ##STR00181##

[0717] To a mixture of 4-iodo-1H-imidazole (10 g, 51.55 mmol, 1 eq) in THF (200 mL) was added NaH (2.27 g, 56.71 mmol, 60 wt % in mineral oil, 1.1 eq) at 0 C. The mixture was stirred at 0 C. for 15 minutes. Then (2-(chloromethoxy)ethyl)trimethylsilane (10.31 g, 61.86 mmol, 1.2 eq) was added. The reaction mixture was stirred at 20 C. for 2 hours, quenched with water (200 mL) and extracted with EtOAc (2200 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 5:1) to give the title compound (7.6 g, 45%) as a yellow oil.

[0718] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.50 (s, 1H), 7.14 (s, 1H), 5.24 (s, 2H), 3.536 (t, 2H), 0.92 (t, 2H), and 0.00 (s, 9H).

[0719] LCMS: m/z 325.0 (M+H).sup.+ (ES.sup.+).

Step B: S-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl) benzothioate and S-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)benzothioate

[0720] ##STR00182##

[0721] A mixture (5.4 g, 16.65 mmol, 1 eq) of 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and 5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole was dissolved in toluene (120 mL). Benzothioic S-acid (2.30 g, 16.65 mmol, 1 eq), DIPEA (8.61 g, 66.62 mmol, 4 eq), CuI (159 mg, 832.73 mol, 0.05 eq) and 1,10-phenanthroline (300 mg, 1.67 mmol, 0.1 eq) were added at 20 C. The mixture was stirred at 120 C. for 5 hours under N.sub.2 and then concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with EtOAc (280 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 5:1) to give the title compounds (2.8 g, mixture, 50%) as a brown oil.

[0722] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.02 (d, 2H), 7.80 (s, 1H), 7.51-7.43 (m, 4H), 5.34 (s, 2H), 3.56 (t, 2H), 0.95 (t, 2H) and 0.01 (s, 9H).

Step C: 4-(Benzylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and 5-(benzylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

[0723] ##STR00183##

[0724] A mixture (1.5 g, 4.48 mmol, 1 eq) of S-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl) benzothioate and S-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl) benzothioate was dissolved in MeOH (15 mL). K.sub.2CO.sub.3 (744 mg, 5.38 mmol, 1.2 eq) and BnBr (767 mg, 4.48 mmol, 1 eq) were added. The reaction mixture was stirred at 20 C. for 0.5 hour under N.sub.2, and then diluted with water (20 mL) and extracted with EtOAc (320 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 5:1 to 3:1) to give the title compounds (840 mg, mixture, 57%) as a yellow oil.

[0725] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.60 (s, 1H), 7.25-7.19 (m, 5H), 6.83 (s, 1H), 5.16 (s, 2H), 4.05 (s, 2H), 3.42 (t, 2H), 0.89 (t, 2H) and 0.015 (s, 9H).

[0726] LCMS: m/z 321.0 (M+H).sup.+ (ES.sup.+).

Step D: 4-(Benzylthio)-1H-imidazole

[0727] ##STR00184##

[0728] A mixture (740 mg, 2.31 mmol, 1 eq) of 4-(benzylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and 5-(benzylthio)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole was dissolved in DCM (6 mL). TFA (6.16 g, 54.02 mmol, 23.40 eq) was added. The reaction mixture was stirred at 20 C. for 4 hours and then concentrated. The residue was diluted with saturated aqueous NaHCO.sub.3 solution (20 mL) and extracted with EtOAc (320 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 5:1 to 0:1) to give the title compound (422 mg, 86% yield, 90% purity on LCMS) as a yellow solid.

[0729] .sup.1H NMR (400 MHz, CD.sub.3OD) 7.69 (s, 1H), 7.21-7.17 (m, 3H), 7.12-7.10 (m, 2H), 6.85 (s, 1H) and 3.92 (s, 2H).

[0730] LCMS: m/z 191.1 (M+H).sup.+ (ES.sup.+).

Step E: 4-(Benzylthio)-1-cyclopropyl-1H-imidazole

[0731] ##STR00185##

[0732] To a mixture of 4-(benzylthio)-1H-imidazole (380 mg, 2.00 mmol, 1 eq) and cyclopropylboronic acid (206 mg, 2.40 mmol, 1.2 eq) in dioxane (6 mL) were added Na.sub.2CO.sub.3 (339 mg, 3.20 mmol, 1.6 eq) and 2,2-bipyridine (312 mg, 2.00 mmol, 1 eq). The reaction mixture was stirred at 20 C. for 0.5 hour. Then Cu(OAc).sub.2 (363 mg, 2.00 mmol, 1 eq) was added. The reaction mixture was heated to 70 C. and stirred for 12 hours. The reaction mixture was diluted with water (20 mL) and filtered. The filtrate was extracted with EtOAc (320 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) to give the title compound (83 mg, 17% yield, 96% purity on LCMS) as a yellow oil.

[0733] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.72 (d, 1H), 7.26-7.18 (m, 5H), 7.06 (d, 1H), 3.98 (s, 2H), 3.45-3.41 (m, 1H) and 0.90-0.86 (m, 4H).

[0734] LCMS: m/z 231.2 (M+H).sup.+ (ES.sup.+).

Step F: 1-Cyclopropyl-1H-imidazole-4-sulfonyl chloride

[0735] ##STR00186##

[0736] To a solution of 4-(benzylthio)-1-cyclopropyl-1H-imidazole (100 mg, 434.16 mol, 1 eq) in AcOH (4 mL) was added NCS (174 mg, 1.30 mmol, 3 eq). The reaction mixture was stirred at 20 C. for 0.5 hour, and then quenched with water (20 mL) and extracted with EtOAc (220 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (100 mg, crude) as a colourless oil, which was used in the next step without further purification.

Step G: 1-Cyclopropyl-1H-imidazole-4-sulfonamide

[0737] ##STR00187##

[0738] To a mixture of 1-cyclopropyl-1H-imidazole-4-sulfonyl chloride (89 mg, crude) in THF (5 mL) was bubbled NH.sub.3 gas (15 psi) at 0 C. for 5 minutes. Then the mixture was stirred at 20 C. for 1 hour, and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) to give the title compound (23 mg, 26% yield, 92% purity on LCMS) as a white solid.

[0739] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.85 (d, 1H), 7.64 (d, 1H), 7.12 (s, 2H), 3.58-3.55 (m, 1H) and 1.00-0.96 (m, 4H).

[0740] LCMS: m/z 188.1 (M+H).sup.+ (ES.sup.+).

Intermediate P5: 1-Cyclopropyl-1H-pyrazole-3-sulfonamide

Step A: 1-Cyclopropyl-3-nitro-1H-pyrazole

[0741] ##STR00188##

[0742] To a solution of cyclopropylboronic acid (36.77 g, 428.04 mmol, 1.1 eq) in DCE (500 mL) was added 3-nitro-1H-pyrazole (44 g, 389.12 mmol, 1 eq), 2,2-bipyridine (60.77 g, 389.12 mmol, 1 eq) and Na.sub.2CO.sub.3 (64.59 g, 609.44 mmol, 1.57 eq) at 25 C. The mixture was stirred at 25 C. for 30 minutes. Then Cu(OAc).sub.2 (70.68 g, 389.12 mmol, 1 eq) was added. The reaction mixture was heated to 70 C. and stirred for 15.5 hours, and then concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 30:1 to 3:1) to give crude product (26.7 g). The crude product was dissolved in pyrrolidine (10 mL) and the resulting mixture was stirred at 70 C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove pyrrolidine. The residue was diluted with H.sub.2O (33 mL) and the pH was adjusted to 5-6 with 1M aqueous HCl solution. The mixture was extracted with EtOAc (350 mL). The combined organic layers were washed with brine (233 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (17.7 g, 30%) as a yellow oil.

[0743] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.54 (d, 1H), 6.84 (d, 1H), 3.73-3.67 (m, 1H), 1.24-1.22 (m, 2H) and 1.13-1.07 (m, 2H).

Step B: 1-Cyclopropyl-1H-pyrazol-3-amine

[0744] ##STR00189##

[0745] To a solution of 1-cyclopropyl-3-nitro-1H-pyrazole (36 g, 235.08 mmol, 1 eq) in EtOH (400 mL) was added a solution of NH.sub.4Cl (62.87 g, 1.18 mol, 5 eq) in H.sub.2 (150 mL). The reaction mixture was heated to 60 C. and iron power (39.38 g, 705.24 mmol, 3 eq) was added in portions. The reaction mixture was stirred at 60 C. for 16 hours, and then concentrated under reduced pressure. The residue was diluted with H.sub.2O (500 mL) and the mixture was extracted with EtOAc (3500 mL). The combined organic layers were washed with brine (2250 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 30:1 to 1:1) to give the title compound (20 g, 69%) as a yellow oil.

[0746] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.14 (d, 1H), 5.11 (d, 1H), 3.57 (br s, 2H), 3.38-3.32 (m, 1H), 0.99-0.95 (m, 2H) and 0.90-0.87 (m, 2H).

[0747] LCMS: m/z 124.2 (M+H).sup.+ (ES.sup.+).

Step C: 1-Cyclopropyl-1H-pyrazole-3-sulfonyl chloride

[0748] ##STR00190##

[0749] To a solution of 1-cyclopropyl-1H-pyrazol-3-amine (19 g, 154.28 mmol, 1 eq) in MeCN (500 mL) and H.sub.2O (50 mL) at 0 C. was added concentrated HCl solution (50 mL, 36 wt % aqueous solution). Then an aqueous solution of NaNO.sub.2 (12.77 g, 185.13 mmol, 1.2 eq) in H.sub.2O (50 mL) was added slowly. The resulting solution was stirred at 0 C. for 40 minutes. AcOH (50 mL), CuCl.sub.2 (10.37 g, 77.14 mmol, 0.5 eq) and CuCl (763 mg, 7.71 mmol, 0.05 eq) were added. Then SO.sub.2 gas (15 psi) was bubbled into the resulting mixture at 0 C. for 20 minutes. The resulting reaction mixture was stirred at 0 C. for 1 hour, and then concentrated under reduced pressure. The residue was diluted with H.sub.2O (250 mL) and extracted with EtOAc (3250 mL). The combined organic layers were washed with brine (2150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 100:0 to 1:1) to give the title compound (14 g, 44%) as a yellow oil.

[0750] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.62 (d, 1H), 6.83 (d, 1H), 3.78-3.72 (m, 1H), 1.28-1.24 (m, 2H) and 1.16-1.12 (m, 2H).

Step D: 1-Cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0751] ##STR00191##

[0752] To a solution of 1-cyclopropyl-1H-pyrazole-3-sulfonyl chloride (28 g, 135.49 mmol, 1 eq) in THF (300 mL) was added TEA (27.42 g, 270.99 mmol, 2 eq) and bis(4-methoxybenzyl)amine (34.87 g, 135.49 mmol, 1 eq). The reaction mixture was stirred at 25 C. for 1 hour, and then diluted with H.sub.2O (500 mL) and extracted with EtOAc (3500 mL). The combined organic layers were washed with brine (2500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by reversed phase flash chromatography (0.5% NH.sub.3.H.sub.2O-MeCN) and the collected eluting solution was concentrated under reduced pressure to remove most of MeCN. Then the mixture was extracted with EtOAc (31). The combined organic layers were washed with brine (2500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (30 g, 52% yield, 99.8% purity on HPLC).

[0753] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.49 (d, 1H), 7.08-7.06 (m, 4H), 6.79-6.77 (m, 4H), 6.62 (d, 1H), 4.32 (s, 4H), 3.80 (s, 6H), 3.68-3.64 (m, 1H), 1.15-1.13 (m, 2H) and 1.9-1.06 (m, 2H).

[0754] LCMS: m/z 428.2 (M+H).sup.+ (ES.sup.+).

Step E: 1-Cyclopropyl-1H-pyrazole-3-sulfonamide

[0755] ##STR00192##

[0756] To a mixture of 1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (1 g, 2.34 mmol, 1 eq) in DCM (10 mL) was added TFA (15.40 g, 135.06 mmol, 57.74 eq).

[0757] The mixture was stirred at 25 C. for 12 hours. Most of the solvent was evaporated and the residue was re-dissolved in MeOH (30 mL). Solids were formed and the suspension mixture was filtered. The filtrate was concentrated in vacuo and then the residue was triturated with a mixture of petroleum ether and EtOAc (30 mL, v:v 20:1) to give the title compound (430 mg, 88% yield, 0% purity on LCMS) as a white solid.

[0758] .sup.1H NMR (DMSO-d.sub.6): 7.92 (s, 1H), 7.38 (br s, 2H), 6.55 (s, 1H), 3.84-3.78 (m, 1H) and 1.10-0.98 (m, 4H).

Intermediate P6: 2-Cyclopropyl-2H-1,2,3-triazole-4-sulfonamide

Step A: 4-(Benzylthio)-1H-1,2,3-triazole

[0759] ##STR00193##

[0760] To a solution of sodium 1H-1,2,3-triazole-4-thiolate (5, 40.61 mmol, 1 eq) in EtOH (50 mL) was added (bromomethyl)benzene (40.61 mmol, 4.82 mL, 1 eq). The mixture was stirred at 15 C. for 12 hours, and then poured into water (200 mL) and extracted with EtOAc (250 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was triturated with petroleum ether (100 mL) to give the title compound (7.25 g, 93%) as a yellow solid.

[0761] .sup.1H NMR (400 MHz, CDCl.sub.3) 11.16 (br s, 1H), 7.51 (s, 1H), 7.32-7.25 (m, 5H) and 4.15 (s, 2H).

[0762] LCMS: m/z 192.1 (M+H).sup.+ (ES.sup.+).

Step B: 4-(Benzylthio)-2-cyclopropyl-2H-1,2,3-triazole

[0763] ##STR00194##

[0764] To a solution of 4-(benzylthio)-1H-1,2,3-triazole (6 g, 31.37 mmol, 1 eq) in dioxane (30 mL) was added Na.sub.2CO.sub.3 (4.99 g, 47.06 mmol, 1.5 eq), cyclopropylboronic acid (5.39 g, 62.74 mmol, 2 eq), 2,2-bipyridine (4.90 g, 31.37 mmol, 1 eq) and Cu(OAc).sub.2 (5.70 g, 31.37 mmol, 1 eq). The reaction mixture was stirred at 80 C. for 12 hours, and then filtered. The filtrate was diluted with EtOAc (400 mL). The organic layer was washed with water (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 20:1) to give the title compound (1.65 g, 23%) as a yellow oil.

[0765] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.72 (s, 1H), 7.30-7.22 (m, 5H), 4.16 (s, 2H), 4.08-4.02 (m, 1H) and 1.14-0.98 (m, 4H).

[0766] LCMS: m/z 232.1 (M+H).sup.+ (ES.sup.+).

Step C: 2-Cyclopropyl-2H-1,2,3-triazole-4-sulfonyl chloride

[0767] ##STR00195##

[0768] To a solution of 4-(benzylthio)-2-cyclopropyl-2H-1,2,3-triazole (1.6 g, 6.92 mmol, 1 eq) in AcOH (40 mL) was added NCS (2.77 g, 20.75 mmol, 3 eq). The reaction mixture was stirred at 20 C. for 1 hour, and then poured into water (150 mL) and extracted with DCM (260 mL). The combined organic layers were washed with brine (360 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (1.44 g, crude) as a yellow oil.

Step D: 2-Cyclopropyl-2H-1,2,3-triazole-4-sulfonamide

[0769] ##STR00196##

[0770] To a solution of 2-cyclopropyl-2H-1,2,3-triazole-4-sulfonyl chloride (1.44 g, crude) in DCM (30 mL) was bubbled NH.sub.3 (15 psi) at 10 C. for 10 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (1.01 g, 77%) as a yellow solid.

[0771] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.07 (s, 1H), 7.79 (br s, 2H), 4.28-4.22 (m, 1H) and 1.23-1.15 (m, 4H).

[0772] LCMS: m/z 189.1 (M+H).sup.+ (ES.sup.+).

Intermediate P7: 1-Cyclopropyl-1H-pyrazole-4-sulfonamide

Step A: 1-Cyclopropyl-4-iodo-1H-pyrazole

[0773] ##STR00197##

[0774] To a mixture of cyclopropylboronic acid (4.87 g, 56.71 mmol, 1.1 eq) in dioxane (150 mL) were added 4-iodo-1H-pyrazole (10 g, 51.55 mmol, 1 eq), 2-(2-pyridyl)pyridine (8.05 g, 51.55 mmol, 1 eq) and Na.sub.2CO.sub.3 (8.74 g, 82.49 mmol, 1.6 eq) in one portion at 25 C. The reaction mixture was stirred for 0.5 hour at 25 C. Then Cu(OAc).sub.2 (9.36 g, 51.55 mmol, 1 eq) was added. The reaction mixture was heated to 70 C. and stirred for another 12 hours under O.sub.2 (15 psi). Then the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 50:1 to 15:1) to give the title compound (2.4 g, 19%) as a yellow oil.

[0775] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.50 (s, 1H), 7.48 (s, 1H), 3.64-3.58 (m, 1H), 1.12-1.09 (m, 2H) and 1.04-1.02 (m, 2H).

Step B: S-(1-Cyclopropyl-1H-pyrazol-4-yl) benzothioate

[0776] ##STR00198##

[0777] To a mixture of 1-cyclopropyl-4-iodo-1H-pyrazole (2.4 g, 10.25 mmol, 1 eq) and benzothioic S-acid (1.49 g, 10.77 mmol, 1.05 eq) in toluene (50 mL) were added 1,10-phenanthroline (92 mg, 512.74 mol, 0.05 eq), CuI (98 mg, 512.74 mol, 0.05 eq) and DIPEA (5.3 g, 41.02 mmol, 4 eq) in one portion under nitrogen. Then the reaction mixture was heated to 120 C. and stirred for another 12 hours. The mixture was quenched with water (100 mL) and extracted with EtOAc (310 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 50:1 to 10:1) to give the title compound (1.34 g, 44% yield, 83% purity on LCMS) as a brown solid.

[0778] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.02-8.00 (m, 2H), 7.66 (s, 1H), 7.62-7.60 (m, 1H), 7.55 (s, 1H), 7.49 (t, 2H), 3.70-3.64 (m, 1H), 1.20-1.19 (m, 2H) and 1.07-1.05 (m, 2H).

[0779] LCMS: m/z 245.1 (M+H).sup.+ (ES.sup.+).

Step C: 1-Cyclopropyl-1H-pyrazole-4-sulfonyl chloride

[0780] ##STR00199##

[0781] To a mixture of S-(1-cyclopropyl-1H-pyrazol-4-yl) benzothioate (1 g, 4.09 mmol, 1 eq) in AcOH (40 mL) and H.sub.2O (4 mL) was added NCS (1.64 g, 12.28 mmol, 3 eq) at 25 C. in one portion. The reaction mixture was stirred for 1 hour, and then quenched with water (80 mL) and extracted with DCM (240 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtrate (theory amount, 0.8 g) was used directly to the next step without further purification.

Step D: 1-Cyclopropyl-1H-pyrazole-4-sulfonamide

[0782] ##STR00200##

[0783] To a solution of 1-cyclopropyl-1H-pyrazole-4-sulfonyl chloride (850 mg, crude) in DCM (80 mL) was bubbled NH.sub.3 (15 psi) at 10 C. for 10 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) to give the title compound (0.3 g, 38% yield, 98.6% purity on LCMS) as a yellow oil.

[0784] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.23 (s, 1H), 7.68 (s, 1H), 7.21 (br s, 2H), 3.83-3.79 (m, 1H), 1.07-1.04 (m, 2H) and 1.01-0.95 (m, 2H).

[0785] LCMS: m/z 188.1 (M+H).sup.+ (ES.sup.+).

Intermediate P8: N-Methyl-N-(1-methylpyrrolidin-3-yl)sulfamide

[0786] ##STR00201##

[0787] Chlorosulfonylisocyanate (1.06 g, 7.5 mmol) was dissolved in DCM (5 mL) at 0 C. under N.sub.2 atmosphere. tert-Butanol (0.56 g, 7.5 mmol) in DCM (5 mL) was added dropwise and the mixture was stirred for 30 minutes at 0 C. N,1-dimethylpyrrolidin-3-amine (0.86 g, 7.5 mmol) and triethylamine (0.83 g, 8.3 mmol) in DCM (10 mL) were added dropwise while maintaining the temperature below 8 C. Then the mixture was allowed to reach room temperature and stirred for 48 hours. DCM (30 mL) and water (30 mL) were added. The layers were separated. The water layer was extracted with further DCM (30 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness. The yellow solid obtained was dissolved in acetonitrile (60 mL) and aqueous 5N HCl (10 mL) was added. The mixture was stirred at 80 C. for 3 hours, and then evaporated to dryness and redissolved in isopropanol (20 mL). Potassium tert-butoxide (0.84 g, 7.5 mmol) was added. The mixture was stirred for 1 hour at room temperature, and then filtered. The filtrate was evaporated to dryness to yield the title compound (1.3 g, 90%) as a light brown oil.

[0788] .sup.1H NMR (300 MHz, DMSO-d6) 4.22 (m, 1H), 2.51 (s, 3H), 2.38 (t, 1H), 2.17 (s, 3H), 2.12 (t, 1H), 1.90 (m, 1H), 1.65 (m, 3H).

[0789] LCMS: m/z 194 (M+H).sup.+ (ES.sup.+).

Intermediate P9: 3-(Diethylamino)propane-1-sulfonamide

[0790] ##STR00202##

[0791] To a microwave vial containing a solution of 3-chloropropane-1-sulfonamide (600 mg, 3.81 mmol) in acetonitrile (12 mL) was added diethylamine (1.58 mL, 15.2 mmol) and potassium carbonate (526 mg, 3.81 mmol) and the vial was sealed. The mixture was heated at 100 C. in a microwave for 2 hours and subsequently heated by conventional heating at 80 C. overnight. Then the solids were filtered off. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO.sub.2, 0-20% 3.5M MeOH/NH.sub.3 in DCM) to afford the title compound (406 mg, 55%) as white solid.

[0792] .sup.1H NMR (300 MHz, CDCl.sub.3) 3.22 (t, 2H), 2.69 (m, 6H), 2.15 (m, 2H), 1.10 (m, 6H).

Intermediate P10: 5-((Dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

[0793] ##STR00203##

[0794] N,N,1-Trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P11) (500 mg, 2.15 mmol) was stirred in THF (10 mL) and a solution of borane tetrahydrofuran complex (1M, 6 mL, 6 mmol) was added dropwise. The mixture was stirred overnight at reflux and then allowed to cool to room temperature. A solution of 1M HCl (aqueous, 6 mL) was added dropwise. The reaction mixture was stirred at 50 C. for 2 hours, and then allowed to cool to room temperature, concentrated and stripped with toluene (210 mL). The residue was dissolved in MeOH and loaded on a column of SCX (8 g). The MeOH was removed by suction and the column was washed with MeOH (215 mL). 0.7N NH.sub.3 in MeOH (20 mL) was added to the column. The column was left standing for 5 minutes, and then washed twice more with 0.7N NH.sub.3 in MeOH (215 mL). The combined filtrates were concentrated to afford the title compound (314 mg, 67%) as a white solid.

[0795] .sup.1H NMR (300 MHz, Chloroform-d) 6.58 (s, 1H), 3.95 (s, 3H), 3.41 (s, 2H), 2.23 (s, 6H).

Intermediate P11: N,N,1-Trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide

Step A: 1-Methyl-1H-pyrazole-3-sulfonyl chloride

[0796] ##STR00204##

[0797] A solution of 1-methyl-1H-pyrazol-3-amine (25 g, 257.42 mmol, 1 eq) in MeCN (600 mL) at 0 C. was treated with concentrated HCl (60 mL) in H.sub.2O (60 mL). Then an aqueous solution of NaNO.sub.2 (21.31 g, 308.90 mmol, 1.2 eq) in H.sub.2O (60 mL) was added slowly. The resulting reaction mixture was stirred at 0 C. for 40 minutes. AcOH (60 mL), CuCl.sub.2 (17.31 g, 128.71 mmol, 0.5 eq) and CuCl (1.27 g, 12.87 mmol, 0.05 eq) were added. Then SO.sub.2 gas (15 psi) was bubbled into the reaction mixture at 0 C. for 15 minutes. The reaction mixture was stirred at 0 C. for 20 minutes, and then concentrated in vacuo to remove most MeCN. Then the reaction mixture was quenched by addition of H.sub.2O (0.6 L) and extracted with EtOAc (20.3 L). The combined organic layers were washed with brine (30.5 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 20:1 to 10:1) to give the title compound (16.45 g, 35%) as a yellow oil.

[0798] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.52 (d, 1H), 6.89 (d, 1H) and 4.07 (s, 3H).

Step B: N,N-bis(4-Methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide

[0799] ##STR00205##

[0800] To a solution of bis(4-methoxybenzyl)amine (99.83 g, 387.96 mmol, 0.91 eq) in THF (1 L) was added TEA (86.28 g, 852.65 mmol, 2 eq), followed by 1-methyl-H-pyrazole-3-sulfonyl chloride (77 g, 426.33 mmol, 1 eq). The reaction mixture was stirred at 25 C. for 12 hours, and then concentrated in vacuo to remove most of THF. The reaction mixture was quenched by addition of 1M aqueous HCl solution (500 mL) and then extracted with EtOAc (2500 mL). The combined organic layers were washed with brine (2600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was triturated with a mixture of petroleum ether and ethyl acetate (70 mL, v:v=5:1) to give the title compound (138 g, 81%) as a white solid.

[0801] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.40 (d, 1H), 7.08 (d, 4H), 6.78 (d, 4H), 6.65-6.63 (m, 1H), 4.32 (s, 4H), 3.98 (s, 3H) and 3.79 (s, 6H).

[0802] LCMS: m/z 402.2 (M+H).sup.+ (ES.sup.+).

Step C: 3-(N,N-bis(4-Methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid

[0803] ##STR00206##

[0804] A solution of N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (100 g, 249.08 mmol, 1 eq) in THF (1.35 L) was cooled to 70 C. Then n-BuLi (2.5 M, 104.61 mL, in THF, 1.05 eq) was added dropwise. The reaction mixture was stirred at 70 C. for 1 hour. Then CO.sub.2 (15 psi) was bubbled into the mixture for 15 minutes. The reaction mixture was stirred at 70 C. for another 1 hour. Then the reaction mixture was quenched with H.sub.2O (1.2 L) and adjusted with 1M aqueous HCl solution to pH 3. Then the reaction mixture was extracted with EtOAc (21 L), washed with brine (21 L), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and ethyl acetate (300 mL, v:v=1:1) to give the title compound (94 g, 84% yield, 99% purity on LCMS) as a white solid.

[0805] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 6.98-7.16 (m, 5H), 6.82 (d, 4H), 4.25 (s, 4H), 4.15 (s, 3H) and 3.72 (s, 6H).

[0806] LCMS: m/z 468.2 (M+Na).sup.+ (ES.sup.+).

Step D: 3-(N,N-bis(4-Methoxybenzyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide

[0807] ##STR00207##

[0808] To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid (100 g, 224.47 mmol, 1 eq), DIPEA (58.02 g, 448.95 mmol, 2 eq) and dimethylamine (2 M, 448.95 mL, in THF, 4 eq) in DMF (1 L) was added T3P (285.69 g, 448.95 mmol, 50% purity in EtOAc, 2 eq) at 25 C. The reaction mixture was stirred for 30 minutes. Then the reaction mixture was quenched by addition of H.sub.2O (2 L) and extracted with EtOAc (21.1 L). The combined organic layers were washed with brine (21.2 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was triturated with a mixture of ethyl acetate and petroleum ether (150 mL, v:v=5:1) to give the title compound (92.7 g, 87% yield, 100% purity on LCMS).

[0809] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.09 (d, 4H), 6.78 (d, 4H), 6.63-6.70 (m, 1H), 4.32 (s, 4H), 4.02 (s, 3H), 3.79 (s, 6H) and 3.11 (d, 6H).

[0810] LCMS: m/z 473.3 (M+H).sup.+ (ES.sup.+).

Step E: N,N,1-Trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide

[0811] ##STR00208##

[0812] To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-N,N,1-trimethyl-H-pyrazole-5-carboxamide (80 g, 169.29 mmol, 1 eq) in DCM (180 mL) was added TFA (381.33 g, 3.34 mol, 19.75 eq). The reaction mixture was stirred at 15 C. for 15 hours, and then concentrated in vacuo. The residue was re-dissolved in dichloromethane (200 mL). The resulting mixture was treated with MeOH (1.2 L) and a solid was precipitated. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was re-dissolved in dichloromethane (150 mL). The resulting mixture was treated with tert-butyl methyl ether (700 mL) and a solid was precipitated. The suspension was filtered and the filter cake was dried to give the title compound (32 g, 81%) as a white solid.

[0813] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.50 (s, 2H), 6.81 (s, 1H), 3.89 (s, 3H) and 3.02 (d, 6H).

[0814] LCMS: m/z 233.2 (M+H).sup.+ (ES.sup.+).

Intermediate P12: 1-Cyclopropyl-1H-1,2,4-triazole-3-sulfonamide

Step A: 3-(Benzylthio)-1H-1,2,4-triazole

[0815] ##STR00209##

[0816] To a solution of 1H-1,2,4-triazole-3-thiol (5 g, 49.44 mmol, 1 eq) in DMF (50 mL) was added (bromomethyl)benzene (5.87 mL, 49.44 mmol, 1 eq). The reaction mixture was stirred at 15 C. for 12 hours, and then poured into water (300 mL) and extracted with EtOAc (3150 mL). The combined organic layers were washed with brine (3100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was triturated with petroleum ether (100 mL) to give the title compound (8.2 g, 87%) as a white solid.

[0817] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 14.05 (br s, 1H), 7.38-7.24 (m, 5H) and 4.35 (s, 2H).

[0818] LCMS: m/z 192.1 (M+H).sup.+ (ES.sup.+).

Step B: 3-(Benzylthio)-1-cyclopropyl-1H-1,2,4-triazole

[0819] ##STR00210##

[0820] To a solution of 3-(benzylthio)-1H-1,2,4-triazole (7 g, 36.60 mmol, 1 eq) in dioxane (200 mL) were added Na.sub.2CO.sub.3 (5.82 g, 54.90 mmol, 1.5 eq), cyclopropylboronic acid (6.29 g, 73.20 mmol, 2 eq), 2,2-bipyridine (5.72 g, 36.60 mmol, 1 eq) and Cu(OAc).sub.2 (6.65 g, 36.60 mmol, 1 eq). The reaction mixture was stirred at 80 C. for 12 hours. The reaction mixture was filtered and the filtrate was diluted with EtOAc (400 mL). The filtrate was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 5:1) to give the title compound (1.7 g, 20%) as a yellow oil.

[0821] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.54 (s, 1H), 7.49-7.29 (m, 5H), 4.45 (s, 2H), 3.82-3.76 (m, 1H) and 1.24-1.18 (m, 4H).

[0822] LCMS: m/z 232.1 (M+H).sup.+ (ES.sup.+).

Step C: 1-Cyclopropyl-1H-1,2,4-triazole-3-sulfonyl chloride

[0823] ##STR00211##

[0824] To a solution of 3-(benzylthio)-1-cyclopropyl-1H-1,2,4-triazole (1.6 g, 6.92 mmol, 1 eq) in AcOH (40 mL) was added NCS (2.77 g, 20.75 mmol, 3 eq). The reaction mixture was stirred at 25 C. for 1 hour, and then poured into water (130 mL) and extracted with DCM (270 mL). The combined organic layers were washed with brine (380 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (theory amount: 1.44 g, crude) as a yellow oil, which was used directly in the next step.

Step D: 1-Cyclopropyl-1H-1,2,4-triazole-3-sulfonamide

[0825] ##STR00212##

[0826] To a solution of 1-cyclopropyl-1H-1,2,4-triazole-3-sulfonyl chloride (1.44 g, crude) in DCM (30 mL) was bubbled NH.sub.3 (15 psi) at 10 C. for 10 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with EtOAc (10 mL) and filtered. The filter cake was collected to give the title compound (750 mg, 57%) as a yellow solid.

[0827] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.79 (s, 1H), 7.75 (br s, 2H), 3.90-3.84 (m, 1H) and 1.16-1.07 (m, 4H).

[0828] LCMS: m/z 189.1 (M+H).sup.+ (ES.sup.+).

Intermediate P13: 1-Isopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

Step A: 1-Isopropyl-3-nitro-1H-pyrazole

[0829] ##STR00213##

[0830] To a mixture of 3-nitro-1H-pyrazole (30 g, 265.31 mmol, 1 eq) in DMF (300 mL) was added NaH (11.14 g, 278.58 mmol, 60% purity in mineral oil, 1.05 eq) in portions at 0 C. Then the reaction mixture was stirred at 0 C. for 0.5 hour. 2-Bromopropane (39.16 g, 318.37 mmol, 1.2 eq) was added and the resulting mixture was warmed to 25 C. for 12 hours. The reaction mixture was quenched with water (500 mL) and extracted with EtOAc (3300 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 50:1 to 2:1) to give the title compound (29.2 g, 71%) as a yellow oil.

[0831] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.49 (d, 1H), 6.90 (d, 1H), 4.63-4.56 (m, 1H) and 1.58 (d, 6H).

Step B: 1-Isopropyl-1H-pyrazol-3-amine

[0832] ##STR00214##

[0833] To a solution of 1-isopropyl-3-nitro-1H-pyrazole (29.2 g, 188.20 mmol, 1 eq) in MeOH (400 mL) was added Pd/C (3 g, 10 wt % loading on activated carbon) under N.sub.2. The suspension was degassed in vacuo and purged with H.sub.2 several times. The reaction mixture was stirred at 25 C. for 2 hours under H.sub.2 (30 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (15.81 g, 66% yield, 98.2% purity on LCMS) as a brown oil.

[0834] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.15 (d, 1H), 5.55 (d, 1H), 4.30-4.20 (m, 1H), 3.61 (s, 2H) and 1.43 (d, 6H).

[0835] LCMS: m/z 126.2 (M+H).sup.+ (ES.sup.+).

Step C: 1-Isopropyl-1H-pyrazole-3-sulfonyl chloride

[0836] ##STR00215##

[0837] To a solution of 1-isopropyl-1H-pyrazol-3-amine (15.8 g, 126.23 mmol, 1 eq) in MeCN (600 mL) at 0 C. was added a solution of HCl (116.57 mL, 11.08 eq, 36 wt % in aqueous solution) in H.sub.2 (50 mL). Then an aqueous solution of NaNO.sub.2 (10.45 g, 151.47 mmol, 1.2 eq) in H.sub.2O (50 mL) was added slowly. The resulting mixture was stirred at 0 C. for 0.75 hour. AcOH (50 mL), CuCl (625 mg, 6.31 mmol, 0.05 eq) and CuCl.sub.2 (8.49 g, 63.11 mmol, 0.5 eq) were added. Then SO.sub.2 gas (15 psi) was bubbled into the mixture at 0 C. for 0.25 hour. The reaction mixture was stirred at 0 C. for 1 hour, and then poured into ice water (500 mL) and extracted with DCM (2700 mL). The combined organic layers were washed with brine (2700 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 10:1) to give the title compound (18.36 g, 70%) as a colourless oil.

[0838] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.56 (d, 1H), 6.88 (d, 1H), 4.70-4.60 (m, 1H) and 1.59 (d, 6H).

Step D: 1-Isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0839] ##STR00216##

[0840] To a mixture of 1-isopropyl-1H-pyrazole-3-sulfonyl chloride (17.3 g, 82.91 mmol, 1 eq) and TEA (10.91 g, 107.78 mmol, 1.3 eq) in THF (200 mL) was added bis(4-methoxybenzyl)amine (14.93 g, 58.04 mmol, 0.7 eq). The reaction mixture was stirred at 20 C. for 3 hours, and then poured into water (500 mL) and extracted with DCM (2500 mL). The combined organic layers were washed with brine (2500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 20:1 to 4:1) to give the title compound (21.13 g, 59% yield, 100% purity on LCMS) as a colourless oil.

[0841] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.46 (d, 1H), 7.09-7.04 (m, 4H), 6.80-6.74 (m, 4H), 6.65 (d, 1H), 4.62-4.54 (m, 1H), 4.32 (s, 4H), 3.79 (s, 6H) and 1.53 (d, 6H).

[0842] LCMS: m/z 452.2 (M+Na).sup.+ (ES.sup.+).

Step E: 5-(3-Hydroxyoxetan-3-yl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0843] ##STR00217##

[0844] To a solution of 1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (12 g, 27.94 mmol, 1 eq) in THF (200 mL) was added dropwise n-BuLi (2.5 M, 12.07 mL, in THF, 1.08 eq) at 78 C. Then the reaction mixture was stirred at 78 C. for 1 hour. A solution of oxetan-3-one (2.07 g, 28.78 mmol, 1.03 eq) in THF (50 mL) was added and the resulting mixture was stirred at 78 C. for 1 hour. The reaction mixture was quenched with saturated aqueous NH.sub.4C1 solution (10 mL), poured into water (500 mL) and extracted with ethyl acetate (2500 mL). The combined organic layers were washed with brine (2500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 2:1) to give the title compound (5.11 g, 35% yield, 96.7% purity on LCMS) as a white solid.

[0845] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.05 (d, 4H), 6.88 (s, 1H), 6.84-6.80 (m, 4H), 6.79 (s, 1H), 4.88 (d, 2H), 4.77 (d, 2H), 4.46-4.38 (m, 1H), 4.23 (s, 4H), 3.72 (s, 6H) and 1.36 (d, 6H).

[0846] LCMS: m/z 502.3 (M+H).sup.+ (ES.sup.+).

Step F: 1-Isopropyl-N,N-bis(4-methoxybenzyl)-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

[0847] ##STR00218##

[0848] To a solution of 5-(3-hydroxyoxetan-3-yl)-1-isopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (9.6 g, 19.14 mmol, 1 eq) in DMF (150 mL) was added portionwise NaH (919 mg, 22.97 mmol, 60 wt % in mineral oil, 1.2 eq) at 0 C. The reaction mixture was stirred at 0 C. for 0.5 hour. Then MeI (10.87 g, 76.56 mmol, 4 eq) was added. The reaction mixture was stirred at 0 C. for 13.5 hours, and then warmed to 20 C. The reaction mixture was quenched with saturated aqueous NH.sub.4C1 solution (10 mL) slowly, poured into water (800 mL) and extracted with ethyl acetate (2500 mL). The combined organic layers were washed with brine (3500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (9.87 g, 94% yield, 94.3% purity on LCMS) as a white solid.

[0849] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.14-7.11 (m, 4H), 6.81-6.77 (m, 4H), 6.60 (s, 1H), 4.91 (d, 2H), 4.80 (d, 2H), 4.36 (s, 4H), 4.32-4.25 (m, 1H), 3.79 (s, 6H), 3.05 (s, 3H) and 1.43 (d, 6H).

[0850] LCMS: m/z 516.3 (M+H).sup.+ (ES.sup.+).

Step G: 1-Isopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

[0851] ##STR00219##

[0852] A solution of 1-isopropyl-N,N-bis(4-methoxybenzyl)-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide (9.8 g, 19.01 mmol, 1 eq) in TFA (40 mL) and DCM (40 mL) was stirred at 16 C. for 20 hours. Then the reaction mixture was concentrated in vacuo. The residue was redissolved in THF (80 mL). Hexane (200 mL) was added to the mixture and some solid was precipitated. The colourless precipitate was collected by filtration, washing with hexane (100 ml) and dried in vacuo to give the title compound (3.5 g, 63% yield, 93.7% purity on LCMS) as a light yellow solid.

[0853] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.46 (s, 2H), 6.86 (s, 1H), 4.86-4.82 (m, 4H), 4.30-4.20 (m, 1H), 3.00 (s, 3H) and 1.37 (d, 6H).

[0854] LCMS: m/z 276.1 (M+H).sup.+ (ES.sup.+).

Intermediate P14: 4-(2-Hydroxypropan-2-yl)thiophene-2-sulfonamide

Step A: Ethyl thiophene-3-carboxylate

[0855] ##STR00220##

[0856] To a mixture of thiophene-3-carboxylic acid (50 g, 390.17 mmol, 1 eq) in EtOH (500 mL) was added H.sub.2SO.sub.4 (78.1 g, 780.34 mmol, 98 wt %, 2 eq). The reaction mixture was stirred at 75 C. for 4 hours, and then concentrated in vacuo to remove most of EtOH. The residue was poured into ice water (500 mL) and extracted with EtOAc (2500 mL). The combined organic layers were washed with saturated aqueous NaHCO.sub.3 solution (500 mL), brine (2800 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (63 g, crude) as a colourless oil, which was used into the next step without further purification.

[0857] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.11 (d, 1H), 7.53 (d, 1H), 7.30 (dd, 1H), 4.33 (q, 2H) and 1.37 (t, 3H).

Step B: Ethyl 5-(chlorosulfonyl)thiophene-3-carboxylate

[0858] ##STR00221##

[0859] To a solution of ethyl thiophene-3-carboxylate (60.9 g, 389.88 mmol, 1 eq) in DCM (500 mL) was added dropwise chlorosulfuric acid (56.8 g, 487.35 mmol, 1.25 eq) at 10 C. over a period of 0.25 hour under N.sub.2. After addition, the reaction mixture was warmed to 25 C. and stirred for 20 hours. Then pyridine (32.4 g, 409.37 mmol, 1.05 eq) was added dropwise at 10 C. The reaction mixture was stirred at 10 C. for 0.1 hour. Then PCl.sub.5 (85.3 g, 409.37 mmol, 1.05 eq) was added in portions at 10 C. over a period of 0.1 hour under N.sub.2. The reaction mixture was stirred at 10 C. for 0.55 hour, and then warmed to 25 C. and stirred for 3 hours. The reaction mixture was poured into ice water (600 mL) and extracted with DCM (2500 mL). The combined organic layers were washed with brine (21 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (92 g, crude) as a colourless oil, which was used into the next step without further purification.

[0860] LCMS: m/z 254.9 (M+H).sup.+ (ES.sup.+).

Step C: Ethyl 5-sulfamoylthiophene-3-carboxylate

[0861] ##STR00222##

[0862] Into a solution of ethyl 5-(chlorosulfonyl)thiophene-3-carboxylate (92 g, 299.79 mmol, 1 eq) in THF (500 mL) was bubbled NH.sub.3 (15 psi) at 0 C. for 15 minutes. The reaction mixture was stirred at 25 C. for 1 hour, and then filtered. The filtrate was concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate and THF (v:v 10:1, 200 mL). Petroleum ether (500 mL) was added slowly, and the resulting mixture was stirred at 25 C. for 24 hours. The suspension was filtered and the filter cake was collected to give the title compound (66.5 g, 94%) as a white solid.

[0863] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.54 (d, 1H), 7.82-7.81 (m, 3H), 4.28 (q, 2H) and 1.28 (t, 3H).

Step D: 4-(2-Hydroxypropan-2-yl)thiophene-2-sulfonamide

[0864] ##STR00223##

[0865] To a mixture of ethyl 5-sulfamoylthiophene-3-carboxylate (66 g, 280.52 mmol, 1 eq) in THF (2.3 L) was added methyl magnesium bromide (3 M, 421 mL, 4.5 eq) dropwise at 10 C. over a period of 0.5 hour under N.sub.2. The reaction mixture was stirred at 0 C. for 0.5 hour, and then warmed to 25 C. and stirred for 15 hours. The reaction mixture was quenched with saturated aqueous NH.sub.4C1 solution (500 mL) slowly, and then extracted with EtOAc (2500 mL). The combined organic layers were washed with brine (21 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 3:1 to 1:1) and then triturated with a mixture of ethyl acetate (100 mL) and petroleum ether (100 mL) to give the title compound (28.6 g, 46% yield, 99% purity on LCMS) as a white solid.

[0866] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.59 (s, 2H), 7.55 (d, 1H), 7.52 (d, 1H), 5.20 (s, 1H) and 1.42 (s, 6H).

[0867] LCMS: m/z 204.0 (MOH).sup.+ (ES.sup.+).

Intermediate P15: 5-(2-Hydroxypropan-2-yl)thiazole-2-sulfonamide

Step A: Methyl 2-mercaptothiazole-5-carboxylate

[0868] ##STR00224##

[0869] A solution of methyl 2-bromothiazole-5-carboxylate (10 g, 45.03 mmol, 1 eq) and NaHS (7.21 g, 90.07 mmol, 70 wt % purity (contained 30% H.sub.2O), 2 eq) in EtOH (100 mL) was stirred at 80 C. for 2 hours. The reaction mixture was poured into ice-water (300 mL) and extracted with ethyl acetate (2300 mL). The combined organic layers were washed with brine (2500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (7.82 g, 90% yield, 91% purity on LCMS) as a light yellow solid, which was used into the next step without further purification.

[0870] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 13.83 (br s, 1H), 8.12 (s, 1H) and 3.77 (s, 3H).

[0871] LCMS: m/z 176.6 (M+H).sup.+ (ES.sup.+).

Step B: Methyl 2-(chlorosulfonyl)thiazole-5-carboxylate

[0872] ##STR00225##

[0873] To a solution of methyl 2-mercaptothiazole-5-carboxylate (5.5 g, 28.56 mmol, 1 eq) in DCM (60 mL) was added NCS (11.44 g, 85.69 mmol, 3 eq) at 0 C. The reaction mixture was stirred at 25 C. for 1 hour, and then poured into ice-water (100 mL) and extracted with DCM (270 mL). The combined organic layers were washed with brine (2100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (6.90 g, crude) as a light yellow oil, which was used into the next step without further purification.

Step C: Methyl 2-sulfamoylthiazole-5-carboxylate

[0874] ##STR00226##

[0875] To a stirred solution of methyl 2-(chlorosulfonyl)thiazole-5-carboxylate (6.90 g, 28.55 mmol, 1 eq) in THF (80 mL) was bubbled NH.sub.3 gas (15 psi) at 0 C. for 0.25 hour. The reaction mixture was stirred at 25 C. for 0.5 hour, and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 5:1 to 3:1) to give the title compound (1.1 g, 16% yield, 92% purity on LCMS) as a light yellow solid.

[0876] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.62 (s, 1H), 8.38 (s, 2H) and 3.89 (s, 3H).

[0877] LCMS: m/z 223.5 (M+H).sup.+ (ES.sup.+).

Step D: 5-(2-Hydroxypropan-2-yl)thiazole-2-sulfonamide

[0878] ##STR00227##

[0879] To a solution of methyl 2-sulfamoylthiazole-5-carboxylate (1 g, 4.50 mmol, 1 eq) in THF (20 mL) was added dropwise MeMgBr (3 M, 6.75 mL, 4.5 eq) at 10 C. under N.sub.2. The reaction mixture was stirred at 0 C. for 0.5 hour, and then warmed to 25 C. and stirred for 15 hours. The reaction mixture was quenched with saturated aqueous NH.sub.4C solution (so mL) slowly and extracted with EtOAc (250 mL. The combined organic layers were washed with brine (270 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 3:1) to give the title compound (0.37 g, 35% yield, 95% purity on LCMS) as a light yellow solid.

[0880] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.99 (s, 2H), 7.81 (s, 1H), 5.92 (s, 1H) and 1.55 (s, 6H).

[0881] LCMS: m/z 223.5 (M+H).sup.+ (ES.sup.+).

Intermediate P16: 2-(2-Hydroxypropan-2-yl)thiazole-5-sulfonamide

Step A: 2-(1,1-Dimethoxyethyl)thiazole

[0882] ##STR00228##

[0883] To a solution of 1-(thiazol-2-yl)ethanone (25 g, 196.60 mmol, 1 eq) in MeOH (350 mL) was added trimethoxymethane (121 g, 1.14 mol, 5.80 eq) and 4-methylbenzenesulfonic acid (35.55 g, 206.43 mmol, 1.05 eq) at 25 C. The reaction mixture was stirred at 50 C. for 12 hours, and then poured into H.sub.2O (400 mL). The reaction mixture was concentrated in vacuo to remove MeOH. The residue was quenched with saturated aqueous Na.sub.2CO.sub.3 solution (200 mL) and extracted with EtOAc (3100 mL). The combined organic layers were washed with brine (2200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (27 g, crude) as a red oil.

[0884] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.84 (d, 1H), 7.33 (d, 1H), 3.27 (s, 6H) and 1.75 (s, 3H).

Step B: 5-Bromo-2-(1,1-dimethoxyethyl)thiazole

[0885] ##STR00229##

[0886] To a solution of 2-(1,1-dimethoxyethyl)thiazole (54 g, 311.72 mmol, 1 eq) in THF (1 L) was added dropwise n-BuLi (2.5 M, 137.16 mL, 1.1 eq) at 78 C. under N.sub.2. The reaction mixture was stirred at 78 C. for 0.5 hour. Then a solution of CBr.sub.4 (113.71 g, 342.89 mmol, 1.1 eq) in THF (250 mL) was added dropwise over 10 minutes. The resulting mixture was stirred at 78 C. for 30 minutes, and then warmed to 0 C. The reaction mixture was filtered and the filtrate was poured into saturated aqueous NH.sub.4C solution (200 mL) and water (200 mL). The aqueous phase was extracted with ethyl acetate (2200 mL). The combined organic layers were washed with brine (2500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 10:1) to afford the title compound (70 g, 83% yield, 90% purity on HNMR) as a yellow oil.

[0887] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.70 (s, 1H), 3.25 (s, 6H) and 1.70 (s, 3H).

Step C: 1-(5-Bromothiazol-2-yl)ethanone

[0888] ##STR00230##

[0889] To a solution of 5-bromo-2-(1,1-dimethoxyethyl)thiazole (70 g, 277.64 mmol, 1 eq) in DCM (500 mL) was added TFA (462 g, 4.05 mol, 14.59 eq) and H.sub.2O (10 g, 555.08 mmol, 2.0 eq) at 25 C. The reaction mixture was stirred at 25 C. for 12 hours, and then concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 15:1) to give the title compound (51 g, 89%) as a red solid.

[0890] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.23 (s, 1H) and 2.60 (s, 3H).

Step D: 1-(5-(Benzylthio)thiazol-2-yl)ethanone

[0891] ##STR00231##

[0892] To a solution of 1-(5-bromothiazol-2-yl)ethanone (20 g, 97.06 mmol, 1 eq), phenylmethanethiol (13.26 g, 106.76 mmol, 1.1 eq), DIPEA (25.09 g, 194.12 mmol, 2 eq) and XantPhos (2.81 g, 4.85 mmol, 0.05 eq) in dioxane (200 mL) was added Pd(dba).sub.2 (2.79 g, 4.85 mmol, 0.05 eq) at 25 C. The reaction mixture was stirred at 100 C. for 12 hours under N.sub.2, and then at 25 C. for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 30:1) to afford the title compound (20 g, 67% yield, 81.5% purity on LCMS) as a yellow solid.

[0893] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.95 (s, 1H), 7.46-7.27 (m, 5H), 4.30 (s, 2H) and 2.56 (s, 3H).

[0894] LCMS: m/z 250.0 (M+H).sup.+ (ES.sup.+).

Step E: 2-Acetylthiazole-5-sulfonyl chloride

[0895] ##STR00232##

[0896] Cl.sub.2 gas (15 psi) was bubbled into a solution of 1-(5-(benzylthio)thiazol-2-yl)ethanone (20 g, 80.21 mmol, 1 eq) in AcOH (360 mL) and H.sub.2O (40 mL) at 0 C. for 45 minutes. The reaction mixture was stirred at 0 C. for 1 hour, and then poured into water (500 mL). The aqueous phase was extracted with ethyl acetate (2200 mL). The combined organic layers were washed with brine (2200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (18 g, crude) as a yellow oil, which was used directly in the next step.

Step F: 2-Acetylthiazole-5-sulfonamide

[0897] ##STR00233##

[0898] NH.sub.3 gas (15 psi) was bubbled into THF (300 mL) at 78 C. for 15 minutes. Then a solution of 2-acetylthiazole-5-sulfonyl chloride (18 g, 79.76 mmol, 1 eq) in THF (50 mL) was added dropwise into the above NH.sub.3/THF solution at 78 C. The reaction mixture was stirred at 25 C. for 30 minutes, and then concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 1:1) to afford the title compound (6.8 g, 41%) as a yellow solid.

[0899] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.41 (s, 1H), 8.17 (br s, 2H) and 2.65 (s, 3H).

[0900] LCMS: m/z 206.9 (M+H).sup.+ (ES.sup.+).

Step G: 2-(2-Hydroxypropan-2-yl)thiazole-5-sulfonamide

[0901] ##STR00234##

[0902] To a solution of 2-acetylthiazole-5-sulfonamide (8.6 g, 41.70 mmol, 1 eq) in THF (200 mL) was added MeMgBr (3 M, 55.60 mL, 4 eq) at 10 C. under N.sub.2. The reaction mixture was stirred at 0 C. for 30 minutes, and then at 20 C. for 2 hours. The reaction mixture was poured into aqueous NH.sub.4C1 solution (500 mL). The aqueous phase was extracted with ethyl acetate (2100 mL). The combined organic phases were washed with brine (2200 mL dried over anhydrous NaSO.sub.4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 1:1) to give the title compound (3.5 g, 38%) as a yellow solid.

[0903] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.01 (s, 1H), 7.81 (br s, 2H), 6.29 (br s, 1H) and 1.51 (s, 6H).

[0904] LCMS: m/z 223.0 (M+H).sup.+ (ES.sup.+).

Intermediate P17: ((1R,2R,4S)-2-Hydroxy-7,7-dimethylbicyclo[2.2.1]heptan-1-yl)methanesulfonamide

[0905] ##STR00235##

[0906] To a solution of LiAlH.sub.4 (62 mg, 1.62 mmol) in dry THF (4 mL) cooled to 70 C. was added dropwise a solution of ((1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonamide (300 mg, 1.3 mmol) in dry THF (2 mL). The reaction mixture was stirred towards room temperature for 2 hours, and then quenched by carefully adding Glauber's salt followed by some water. The mixture was filtered over a glass filter with EtOAc (10 mL). Water (1 mL) was added to the filtrate. The organic phase was separated, dried (Na.sub.2SO.sub.4), filtered and concentrated to afford the title compound (77 mg, 25%) as a white solid.

[0907] .sup.1H NMR (300 MHz, Chloroform-d) 3.63 (d, 1H), 3.17-3.00 (m, 2H), 1.99-1.82 (m, 1H), 1.82-1.64 (m, 4H), 1.56-1.43 (m, 2H), 1.08 (s, 3H), 0.84 (s, 3H).

Intermediate P18: 4-Hydroxy-4-methylpentane-1-sulfonamide

[0908] ##STR00236##

[0909] To a solution of methyl 4-sulfamoylbutanoate (750 mg, 4.14 mmol, 1 eq) in anhydrous tetrahydrofuran (15 mL) was added dropwise methyl magnesium bromide (3M solution in diethyl ether, 2.8 mL, 8.28 mmol, 2 eq). After stirring overnight at room temperature, the reaction mixture was quenched with a saturated solution of ammonium chloride. The aqueous solution was extracted four times with ethyl acetate. The organic layers were combined and dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was dissolved in anhydrous tetrahydrofuran (15 mL) and then methyl magnesium bromide (3M solution in diethyl ether, 2.8 mL, 8.28 mmol, 2 eq) was added dropwise. After stirring for six days at room temperature, more methyl magnesium bromide (3M solution in diethyl ether, 2.8 mL, 8.28 mmol, 2 eq) was added. After stirring for one more day, the reaction mixture was quenched with water. The aqueous solution was extracted three times with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and then concentrated in vacuo. The crude product was dissolved in methanol, coated on Agilient hydromatrix (a high purity, inert diatomaceous earth sorbent) and then submitted to normal phase flash chromatography using dichloromethane and ammonia (3.5 M) in methanol to afford the title compound (121 mg, 668 mol, 16%).

[0910] .sup.1H NMR (300 MHz, CDCl.sub.3) 4.57 (s, 2H), 3.20-2.96 (m, 2H), 2.11-1.83 (m, 2H), 1.72-1.54 (m, 2H), 1.23 (s, 6H).

Intermediate P19: 4-Fluoro-3-(2-hydroxypropan-2-yl)benzenesulfonamide

[0911] ##STR00237##

[0912] A solution of methyl 2-fluoro-5-sulfamoylbenzoate (250 mg, 1.07 mmol) in THF (20 mL) was cooled to 20 C. A solution of methyl magnesium bromide (8 mL, 3 M) was added dropwise and the reaction mixture was stirred for 20 hours at room temperature. The mixture was poured into saturated ammonium chloride solution and acidified to pH 4-5 with acetic acid. The water layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to afford the title compound (150 mg, 60%) as a pale yellow solid.

[0913] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.25 (dd, 1H), 7.82 (m, 1H), 7.21 (dd, 1H), 1.59 (s, 6H).

Intermediate P20: 4-(2-Hydroxypropan-2-yl)benzenesulfonamide

[0914] ##STR00238##

[0915] Methyl 4-sulfamoylbenzoate (800 mg, 4.02 mmol) was stirred in THF (20 mL) and a solution of methyl magnesium bromide in Et.sub.2O (3M, 5 mL, 12 mmol) was added dropwise. The mixture was stirred at room temperature for 2 days and poured into saturated NaHCO.sub.3 (aqueous, 20 mL). The mixture was concentrated partially (THF removal) and filtered. EtOAc (20 mL) was used to wash the residual solid and extract the filtrate. The organic phase was separated, dried over Na.sub.2SO.sub.4, filtered and concentrated to afford the title compound (0.7 g, containing 40% starting material, 49% yield) as a white solid.

[0916] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 7.91-7.77 (d, 2H), 7.65 (d, 2H), 1.54 (s, 6H).

Intermediate P21: 3-(2-Cyanopropan-2-yl)benzenesulfonamide

Step A: 3-(Cyanomethyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide

[0917] ##STR00239##

[0918] To a solution of 3-(cyanomethyl)benzenesulfonamide (150 mg, 0.76 mmol) in 2-butanone (20 mL) were added potassium carbonate (211 mg, 1.53 mmol) and 1-(chloromethyl)-4-methoxybenzene (359 mg, 2.29 mmol). The mixture was refluxed for 15 hours. The solvent was evaporated. The residue was extracted with water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified over silica using ethyl acetate/heptane as the eluent to afford the title compound (110 mg, 33%) as a colourless oil.

[0919] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.80 (m, 1H), 7.62 (s, 1H), 7.50 (m, 2H), 6.99 (d, 4H), 6.79 (d, 4H), 4.28 (s, 4H) 3.79 (s, 6H), 3.75 (s, 2H).

Step B: 3-(2-Cyanopropan-2-yl)-N,N-bis(4-methoxybenzyl)benzene sulfonamide

[0920] ##STR00240##

[0921] A solution of 3-(cyanomethyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide (110 mg, 0.25 mmol) in THF (15 mL) was cooled to 0 C. NaH (30 mg, 60% emulsion, 0.75 mmol) was added. After 15 minutes stirring at 0 C., methyl iodide (230 mg. 1.62 mmol) was added. The reaction was stirred for 18 hours at room temperature, and then poured into saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified over silica using ethyl acetate/heptane as the eluent to afford the title compound (45 mg, 38%) as a colourless oil.

[0922] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.81 (m, 1H), 7.75 (m, 2H), 7.55 (t, 1H), 6.97 (d, 4H), 6.78 (d, 4H), 4.28 (s, 4H) 3.78 (s, 6H), 1.71 (s, 6H).

[0923] LCMS: m/z 523.4 (M+OAc.sup.).sup.+ (ES.sup.+).

Step C: 3-(2-Cyanopropan-2-yl)benzenesulfonamide

[0924] ##STR00241##

[0925] 3-(2-Cyanopropan-2-yl)-N,N-bis(4-methoxybenzyl)benzene sulfonamide (45 mg, 0.10 mmol) was dissolved in TFA (5 ml) and the reaction was stirred for 2 days at room temperature. The TFA was evaporated and the residue was triturated in water. The aqueous layer was lyophilized to afford the title compound (17 mg, 85%) as a colourless oil.

[0926] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.07 (t, 1H), 7.88 (m, 1H), 7.78 (m, 1H), 7.63 (t, 1H), 1.76 (s, 6H).

Intermediate P22: 3-Fluoro-4-(2-hydroxypropan-2-yl)benzenesulfonamide

[0927] ##STR00242##

[0928] Methyl 2-fluoro-4-sulfamoylbenzoate (200 mg, 0.92 mmol) was stirred in THF (20 mL) and a solution of methyl magnesium bromide in Et.sub.2O (3M, 2 mL, 6 mmol) was added dropwise. The mixture was stirred at room temperature for 2 days, poured into saturated NaHCO.sub.3 (aqueous, 20 mL), concentrated partially (THF removal) and filtered. DCM (20 mL) was used to wash the residual solid and extract the filtrate. The organic phase was separated, dried over Na.sub.2SO.sub.4, filtered and concentrated to afford the title compound (85 mg, 40%) as a white solid.

[0929] .sup.1H NMR (300 MHz, Chloroform-d) 7.86-7.68 (m, 2H), 7.61 (d, 1H), 1.66 (d, 6H).

Intermediate P23: 3-(2-Hydroxypropan-2-yl)benzenesulfonamide

[0930] ##STR00243##

[0931] A solution of methyl 3-sulfamoylbenzoate (100 mg, 0.47 mmol) in THF (15 ml) was cooled to 0 C. A solution of methyl magnesium bromide in THF (1 ml, 3M) was added dropwise. The reaction mixture was stirred for 2 days at room temperature, and then poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to afford the title compound (90 mg, 90%) as an off white solid.

[0932] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.1 (s, 1H), 7.80 (d, 1H), 7.68 (d, 1H), 7.48 (t, 1H), 1.60 (s, 6H).

Intermediate P24: tert-Butyl (2-(2-fluoro-4-sulfamoylphenyl)propan-2-yl)carbamate

[0933] ##STR00244##

[0934] 4-(2-Aminopropan-2-yl)-3-fluorobenzenesulfonamide (310 mg, 1.33 mmol) was stirred in DCM (6 mL) and EtOH (1 mL). Triethylamine (0.2 mL, 0.47 mmol) was added, followed by Boc anhydride (320 mg, 1.47 mmol). The reaction mixture was stirred overnight. The reaction mixture was diluted with DCM (5 mL), and then washed with water (2 mL), 1M citric acid (aqueous) and brine. The organic phase was separated and dried over Na.sub.2SO.sub.4, filtered and concentrated to afford the title compound (404 mg, 91%) as a colourless oil/foam.

[0935] .sup.1H NMR (300 MHz, Chloroform-d) 7.65 (dd, 1H), 7.60-7.45 (m, 2H), 1.69 (d, 6H), 1.38 (d, 9H).

Intermediate P25: 4-(2-(Dimethylamino)propan-2-yl)-3-fluorobenzenesulfonamide

[0936] ##STR00245##

[0937] 4-(2-Aminopropan-2-yl)-3-fluorobenzenesulfonamide (140 mg, 0.6 mmol) was stirred in water (0.5 mL) and formic acid (0.28 mL, 7.23 mmol). Formaldehyde (0.27 mL of 37% solution in water, 3.62 mmol) was added. The mixture was refluxed for 13 hours, and then concentrated. The residue was dissolved in water (1 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (22 mg, 14%).

[0938] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 7.83-7.73 (m, 1H), 7.66 (m, 1H), 7.63-7.49 (m, 1H), 2.75 (s, 6H), 1.53 (t, 6H).

Intermediate P26: 3-Chloro-4-(2-hydroxypropan-2-yl)benzenesulfonamide

[0939] ##STR00246##

[0940] Methyl 2-chloro-4-sulfamoylbenzoate (302 mg, 1.21 mmol) was stirred in THF (20 mL) and a solution of methyl magnesium bromide in Et.sub.2O (3M, 2 mL, 6 mmol) was added dropwise. The mixture was stirred at room temperature for 2 days, and then poured into saturated NaHCO.sub.3 (aqueous, 10 mL), concentrated partially (THF removal) and filtered. EtOAc (20 mL) was used to wash the residual solid and extract the filtrate. The organic phase was separated, dried over Na.sub.2SO.sub.4, filtered and concentrated to afford the title compound (0.24 g, 80%) as a light yellow solid.

[0941] .sup.1H NMR (300 MHz, Chloroform-d) 7.99-7.90 (m, 2H), 7.87-7.72 (m, 1H), 1.75 (s, 6H).

Intermediate P27: 4-(2-Hydroxypropan-2-yl)furan-2-sulfonamide

Step A: Ethyl furan-3-carboxylate

[0942] ##STR00247##

[0943] To a mixture of furan-3-carboxylic acid (50 g, 446.10 mmol, 1 eq) in EtOH (500 mL) was added dropwise H.sub.2SO.sub.4 (89.29 g, 892.20 mmol, 98 wt %, 2 eq) at 25 C. Then the reaction mixture was heated to 75 C. and stirred for 2.5 hours. The mixture was poured into ice water (200 mL) and extracted with EtOAc (3200 mL). The combined organic layers were washed with 20% aqueous NaHCO.sub.3 solution (2200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (50 g, 80%) as a yellow oil.

[0944] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.02 (d, 1H), 7.43 (t, 1H), 6.75 (t, 1H), 4.31 (q, 2H) and 1.36 (t, 3H).

Step B: 4-(Ethoxycarbonyl)furan-2-sulfonic acid

[0945] ##STR00248##

[0946] To a mixture of ethyl furan-3-carboxylate (45 g, 321.12 mmol, 1 eq) in DCM (500 mL) was added dropwise chlorosulfuric acid (46.77 g, 401.39 mmol, 1.25 eq) at 10 C. under N.sub.2. After 15 minutes, the reaction mixture was stirred at 20 C. for 24 hours. The reaction mixture was filtered and the filter cake was dried in vacuo to give the title compound (55 g, 78%) as a white solid.

[0947] .sup.1H NMR (400 MHz, D.sub.2O) 8.19 (s, 1H), 7.10 (s, 1H), 4.27 (q, 2H) and 1.27 (t, 3H).

Step C: Ethyl 5-(chlorosulfonyl)furan-3-carboxylate

[0948] ##STR00249##

[0949] To a mixture of 4-(ethoxycarbonyl)furan-2-sulfonic acid (55 g, 249.77 mmol, 1 eq) in DCM (350 mL) was added dropwise pyridine (20.74 g, 262.26 mmol, 1.05 eq) at 10 C. under N.sub.2. After 15 minutes, PCl.sub.5 (54.61 g, 262.26 mmol, 1.05 eq) was added and the resulting mixture was stirred at 10 C. for 15 minutes. Then the reaction mixture was warmed to 20 C. and stirred for 12 hours. The mixture was quenched with water (200 mL) and extracted with DCM (2200 mL). Then the combined organic layers were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (35 g, 59%) as a yellow oil, which was used directly into the next step without further purification.

Step D: Ethyl 5-sulfamoylfuran-3-carboxylate

[0950] ##STR00250##

[0951] Into a solution of ethyl 5-(chlorosulfonyl)furan-3-carboxylate (35 g, 146.66 mmol, 1 eq) in DCM (300 mL) was bubbled NH.sub.3 (15 psi) at 0 C. for 15 minutes. Then the reaction mixture was stirred at 20 C. for 45 minutes. The mixture was filtered and the filtrate was concentrated in in vacuo. The residue was triturated with DCM (200 mL). The suspension was filtered, and the filter cake was dried in vacuo to give the title compound (24 g, 75%) as a white solid.

[0952] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.63 (s, 1H), 7.93 (s, 2H), 7.12 (s, 1H), 4.27 (q, 2H) and 1.28 (t, 3H).

Step E: 4-(2-Hydroxypropan-2-yl)furan-2-sulfonamide

[0953] ##STR00251##

[0954] To a mixture of ethyl 5-sulfamoylfuran-3-carboxylate (24 g, 109.48 mmol, 1 eq) in THF (500 mL) was added dropwise MeMgBr (3 M, 164.22 mL, 4.5 eq) at 10 C. over a period of 30 minutes under N.sub.2. The mixture was stirred at 0 C. for 30 minutes, then warmed to 20 C. and stirred for 12 hours. The mixture was poured into ice water (300 mL) slowly and extracted with EtOAc (2300 mL). The organic layers were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by trituration with a mixture of n-hexane and EtOAc (v:v 20:1, 300 mL). The suspension was filtered and the filter cake was dried in vacuo to give the title compound (22 g, 97% yield, 99.3% purity on LCMS) as a white solid.

[0955] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.68 (s, 1H), 7.65 (br s, 2H), 6.95 (s, 1H), and 1.39 (s, 6H).

SYNTHESIS OF EXAMPLES

Example 1: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((1-methyl-6-oxo-,6-dihydropyridin-3-yl)sulfonyl)acetamide, potassium salt

[0956] ##STR00252##

[0957] 1-Methyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate Pi) (20 mg, 0.11 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (62 mg, 0.11 mmol) were stirred in DCM (6 mL). EDC (71 mg, 0.37 mmol) and DMAP (45 mg, 0.37 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KO.sup.tBu (48 mg, 0.43 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (31 mg, 62%) as a white solid.

[0958] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.22 (d, 1H), 8.05 (dd, 1H), 7.84 (dd, 1H), 7.08-6.95 (m, 1H), 6.86 (dd, 1H), 6.78-6.67 (m, 2H), 6.52 (d, 1H), 3.90 (s, 3H), 3.58 (s, 3H), 3.42 (s, 2H), 3.08-2.95 (m, 1H), 1.12 (d, 6H).

[0959] LCMS: m/z 474 (M+H).sup.+ (ES.sup.+); 472 (MH).sup. (ES.sup.).

Example 2: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((1-isopropyl-6-oxo-,6-dihydropyridin-3-yl)sulfonyl)acetamide, potassium salt

[0960] ##STR00253##

[0961] 1-Isopropyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate P2) (17 mg, 0.079 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (24 mg, 0.079 mmol) were stirred in DCM (6 mL). EDC (30 mg, 0.16 mmol) and DMAP (19 mg, 0.16 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.3 mL) and KOtBu (26 mg, 0.24 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (20 mg, 51%) as a white solid.

[0962] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.27 (d, 1H), 8.04 (dd, 1H), 7.79 (dd, 1H), 7.02 (dd, 1H), 6.88 (dd, 1H), 6.77-6.69 (m, 2H), 6.52 (d, 1H), 5.14 (m, 1H), 3.89 (s, 3H), 3.41 (s, 2H), 3.10-2.94 (m, 1H), 1.40 (d, 6H), 1.12 (d, 6H).

[0963] LCMS: m/z 502 (M+H).sup.+ (ES.sup.+); 500 (MH).sup. (ES.sup.).

Example 3: N-((1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide

[0964] ##STR00254##

[0965] 1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-sulfonamide (35 mg, 0.16 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (48 mg, 0.16 mmol) were stirred in DCM (6 mL). EDC (61 mg, 0.32 mmol) and DMAP (39 mg, 0.32 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1), followed by a second purification with the same method to afford the title compound (14 mg, 17%) as a white solid.

[0966] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.26 (s, 1H), 8.14-8.03 (m, 1H), 7.04 (dd, 1H), 6.98-6.84 (m, 1H), 6.81-6.67 (m, 2H), 3.90 (s, 3H), 3.47 (s, 2H), 3.44 (s, 3H), 3.21 (s, 3H), 3.18-3.00 (m, 1H), 1.15 (d, 6H).

[0967] LCMS: m/z 505 (M+H).sup.+ (ES.sup.+); 503 (MH).sup. (ES.sup.).

[0968] The compounds of examples 4-19 were synthesised by methods analogous to those outlined above and below.

TABLE-US-00007 TABLE 1 .sup.1H NMR and MS data 1H NMR Ex Structure and Name spectrum MS MW 4 [00255] .sup.1H NMR (300 MHz, Methanol- d.sub.4) 8.03 (d, 1 H), 7.88 (t, 1 H), 7.35- 7.22 (m, 2 H), 7.00 (dd, 1 H), 6.87 (dd, 1 H), 6.74 (s, 1 H), 6.72 (dd, 1 H), 3.91 (s, 3 H), 3.42 (s, 2 H), 3.03 (m, 1 H), 1.12 (d, 6 H). m/z 495.1 (M + H).sup.+ (ES.sup.+); 493.2 (M H).sup. (ES.sup.). 494.94 5 [00256] .sup.1H NMR (300 MHz, Methanol- d.sub.4) 8.03 (d, 1 H), 7.93 (s, 1 H), 7.82 (d, 1 H), 7.52-7.40 (m, 2 H), 7.01 (dd, 1 H), 6.85 (dd, 1 H), 6.76 (s, 1 H), 6.72 (dd, 1 H), 3.90 (s, 3 H), 3.41 (s, 2 H), 2.99 (m, 1 H), 1.07 (d, 6 H). m/z 477.2 (M + H).sup.+ (ES.sup.+); 475.2 (M H).sup. (ES.sup.). 476.95 6 [00257] .sup.1H NMR (300 MHz, Methanol- d.sub.4) 8.05 (d, 1 H), 7.99 (d, 1 H), 7.50 (d, 1 H), 7.20 (t, 2 H), 7.00 (dd, 1 H), 6.83 (dd, 1 H), 6.78 (s, 1 H), 6.71 (dd, 1 H), 3.91 (s, 3 H), 3.42 (s, 2 H), 2.97 (m, 1 H), 2.63 (s, 1 H), 1.04 (d, 6 H). m/z 491.2 (M + H).sup.+ (ES.sup.+); 489.2 (M H).sup. (ES.sup.). 490.97 7 [00258] .sup.1H NMR (300 MHz, Methanol- d.sub.4) 8.12-8.08 (m, 2 H), 7.52-7.32 (m, 3 H), 6.99 (dd, 1 H), 6.88 (dd, 1 H), 6.76 (s, 1 H), 6.71 (dd, 1 H), 3.91 (s, 3 H), 3.47 (s, 2 H), 3.04 (m, 1 H), 1.04 (d, 6 H). m/z 477.2 (M + H).sup.+ (ES.sup.+); 475.1 (M H).sup. (ES.sup.). 476.95 8 [00259] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.06 (d, 1H), 7.56 (d, 1H), 7.11 (d, 1H), 7.05 (dd, 1H), 6.84 (dd, 1H), 6.80- 6.68 (m, 2H), 3.89 (s, 3H), 3.53 (s, 2H), 3.03-2.89 (m, 1H), 1.62 (s, 6H), 1.13 (d, 6H). m/z 507.0 (M + H).sup.+ (ES.sup.+); 505.2 (M H).sup. (ES.sup.). 506.61 9 [00260] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.12-7.96 (m, 2H), 7.86 (d, 1H), 7.01 (dd, 1H), 6.83 (m, 2H), 6.72 (m, 2H), 3.93 (s, 3H), 3.88 (s, 3H), 3.43 (s, 2H), 2.97 (m, 1H), 1.13-1.07 (d, 6H). m/z 535.0 (M + H).sup.+ (ES.sup.+); 533.2 (M H).sup. (ES.sup.). 534.98 10 [00261] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.28 (dd, 1H), 7.77 (dd, 1H), 7.63 (d, 1H), 7.40 (d, 1H), 7.35 (dd, 1H), 7.05 (dd, 1H), 6.76 (dd, 1H), 3.40 (s, 2H), 3.10 (d, 1H), 1.51 (s, 6H), 1.14 (d, 6H). m/z 493.0 (M 18).sup.+ (ES.sup.+); 509.0 (M H).sup. (ES.sup.). 511.02 11 [00262] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.07-7.96 (m, 2H), 7.79 (dd, 1H), 7.60 (d, 1H), 7.00 (dd, 1H), 6.84 (dd, 1H), 6.76-6.64 (m, 2H), 3.89 (s, 3H), 3.42 (s, 2H), 3.03-2.90 (m, 1H), 1.09 (d, 6H). m/z 511.0 (M + H).sup.+ (ES.sup.+); 509.0 (M H).sup. (ES.sup.). 511.39 12 [00263] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.11-8.04 (m, 1H), 7.84 (d, 1H), 7.11 (d, 1H), 7.07- 6.93 (m, 2H), 6.88 (dd, 1H), 6.75 (d, 1H), 6.70 (dd, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.45 (s, 2H), 3.03 (m, 1H), 1.11 (d, 6H). m/z 507.0 (M + H).sup.+ (ES.sup.+); 505.0 (M H).sup. (ES.sup.). 506.97 13 [00264] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.11-8.00 (m, 2H), 7.53 (d, 1H), 7.37 (dd, 1H), 6.99 (dd, 1H), 6.87 (dd, 1H), 6.77-6.64 (m, 2H), 3.91 (s, 3H), 3.48 (s, 2H), 3.13-2.95 (m, 1H), 1.10 (d, 6H). m/z 511.0 (M + H).sup.+ (ES.sup.+); 509.0 (M H).sup. (ES.sup.). 511.39 14 [00265] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.02 (d, 1H), 7.79 (d, 1H), 6.98 (dd, 1H), 6.83 (d, 1H), 6.75 (s, 1H), 6.68 (dd, 1H), 6.60- 6.44 (m, 2H), 3.88 (s, 3H), 3.44 (s, 2H), 2.99 (m, 1H), 2.98 (s, 6H), 2.55 (s, 3H), 1.09 (d, 6H). m/z 500.2 (M + H).sup.+ (ES.sup.+); 498.2 (M H).sup. (ES.sup.). 499.6 15 [00266] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.10-7.99 (m, 2H), 7.32-7.21 (m, 2H), 6.98 (dd, 1H), 6.84 (dd, 1H), 6.74- 6.63 (m, 2H), 3.91 (s, 3H), 3.47 (s, 2H), 3.09 (s, 3H), 3.04 (m, 1H), 2.96 (s, 3H), 2.63 (s, 3H), 1.10 (d, 6H). m/z 528.2 (M + H).sup.+ (ES.sup.+); 526.2 (M H).sup. (ES.sup.). 527.61 16 [00267] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.48-8.38 (m, 2H), 7.93-7.82 (m, 2H), 7.52-7.41 (m, 2H), 7.37-7.27 (m, 2H), 7.02 (dd, 1H), 6.73 (dd, 1H), 3.39 (s, 2H), 2.99 (dd, 1H), 1.09 (d, 6H). m/z 447.0 (M + H).sup.+ (ES.sup.+); 445.0 (M H).sup. (ES.sup.). 446.92 17 [00268] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.52-8.39 (m, 2H), 7.91-7.83 (m, 2H), 7.74 (dt, 1H), 7.49-7.42 (m, 2H), 7.35 (ddd, 1H), 7.01 (dd, 1H), 6.73 (dd, 1H), 3.39 (s, 2H), 3.08-2.88 (m, 1H), 1.08 (d, 6H). m/z 447.0 (M + H).sup.+ (ES.sup.+); 445.0 (M H).sup. (ES.sup.). 446.92 18 [00269] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.04 (d, 1H), 7.74 (d, 2H), 7.61 (d, 2H), 6.98 (dd, 1H), 6.87 (d, 1H), 6.80 (s, 1H), 6.70 (dd, 1H), 3.90 (s, 3H), 3.44 (s, 2H), 3.14- 3.02 (m, 1H), 1.09 (dd, 6H). m/z 487.0 (M + H).sup.+ (ES.sup.+); 485.2 (M H).sup. (ES.sup.). 486.32 19 [00270] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.01 (dd, 1H), 7.86-7.77 (m, 2H), 7.66-7.57 (m, 2H), 7.00 (dd, 1H), 6.81 (dd, 1H), 6.76-6.67 (m, 2H), 3.89 (s, 3H), 3.42 (s, 2H), 2.97 (m, 1H), 1.09 (d, 6H). m/z 521.0 (M + H).sup.+ (ES.sup.+); 519.0 (M H).sup. (ES.sup.). 521.4

Example 20: N-((4-(2-Hydroxypropan-2-yl)thiophen-2-yl)sulfonyl)-2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetamide

[0969] ##STR00271##

[0970] A solution of 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate P14) (75 mg, 0.34 mmol, 2 eq) and triethylamine (94 L, 0.68 mmol, 4 eq) in dichloromethane (3 mL) was cooled in an ice bath. Then a solution of 2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-H-inden-4-yl)acetyl chloride (Intermediate A2) (51 mg, 0.17 mmol, 1 eq) in anhydrous dichloromethane (3 mL) was added dropwise. After complete addition, the ice bath was removed and the reaction mixture was stirred at room temperature. After stirring over the weekend, the reaction mixture was concentrated in vacuo. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (4 mg, 8 mol, 28%).

[0971] .sup.1H NMR (300 MHz, CD.sub.3OD) 7.99 (d, 1H), 7.66 (d, 1H), 7.42 (d, 1H), 7.12 (d, 1H), 6.97 (d, 1H), 6.87 (dd, 1H), 6.77 (s, 1H), 3.88 (s, 3H), 3.44 (s, 2H), 2.91 (t, 2H), 2.76 (t, 2H), 2.03 (p, 2H), 1.51 (s, 6H).

[0972] LC-MS: m/z 487 (M+H).sup.+ (ES.sup.+).

Example 21: 2-(5-(2-Cyanopyridin-4-yl)-2,3-dihydro-H-inden-4-yl)-N-((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)acetamide

[0973] ##STR00272##

[0974] To a solution of 1-isopropyl-1H-pyrazole-3-sulfonamide, trifluoroacetate salt (73 mg, 0.24 mmol, 2 eq) in anhydrous dichloromethane (2 mL) was added triethylamine (67 L, 0.48 mmol, 4 eq). The solution was cooled in an ice bath. Then a solution of 2-(5-(2-cyanopyridin-4-yl)-2,3-dihydro-H-inden-4-yl)acetyl chloride (Intermediate A3) (36 mg, 0.12 mmol, 1 eq) in anhydrous dichloromethane (2 mL) was added dropwise. After complete addition, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature. After stirring overnight, the reaction mixture was concentrated in vacuo. The crude product was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (3.2 mg, 7.1 mol, 6%).

[0975] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.63 (dd, 1H), 7.80 (dd, 1H), 7.76 (d, 1H), 7.57 (dd. 1H), 7.22 (d, 1H), 7.04 (d, 1H), 6.73 (d, 1H), 4.60 (m, 1H), 3.51 (s, 2H), 2.95 (t, 2H), 2.79 (t, 2H), 2.05 (m, 2H), 1.50 (d, 6H).

[0976] LCMS: m/z 450 (M+H).sup.+ (ES.sup.+).

Example 22: 2-(5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)-N-((4-(2-hydroxypropan-2-yl)thiophen-2-yl)sulfonyl)acetamide

[0977] ##STR00273##

[0978] To a solution of 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate P14) (53 mg, 0.24 mmol, 2 eq) in anhydrous dichloromethane (2 mL) was added triethylamine (50 L, 0.36 mmol, 3 eq). The solution was cooled in an ice bath. Then a solution of 2-(5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetyl chloride (Intermediate A3) (36 mg, 0.12 mmol, 1 eq) in anhydrous dichloromethane (2 mL) was added dropwise. After complete addition, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature. After stirring overnight, the reaction mixture was concentrated in vacuo. The crude product was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (8 mg. 17 mol. 13%).

[0979] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.56 (dd, 1H), 7.85 (dd, 1H), 7.65 (d, 1H), 7.59 (dd, 1H), 7.44 (d, 1H), 7.18 (d, 1H), 7.01 (d, 1H), 3.43 (s, 2H), 2.94 (t, 2H), 2.80 (t, 2H), 2.05 (p, 2H), 1.51 (s, 6H).

[0980] LCMS: m/z 480 (MH).sup. (ES.sup.).

Example 23: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)acetamide, potassium salt

[0981] ##STR00274##

[0982] 1-Isopropyl-1H-pyrazole-3-sulfonamide (76 mg, 0.4 mmol) and triethylamine (0.11 mL, 0.8 mmol) were stirred in DCM (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride (Intermediate A4) (64 mg, 0.2 mmol) in DCM (1 mL) was added dropwise. The reaction mixture was stirred overnight at room temperature and then concentrated. The residue was dissolved in DMSO (0.5 mL) and KOtBu (45 mg, 0.4 mmol) was added. The mixture was filtered over cotton wool and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford crude product (13 mg). The crude product was further purified using preparative HPLC (see Experimental Methods, Purification Method 2) to afford the title compound (3 mg, 3%) as a white solid.

[0983] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.06 (dd, 1H), 7.66 (d, 1H), 7.03 (dd, 1H), 6.90 (dd, 1H), 6.77 (dd, 1H), 6.75 (dd, 1H), 6.67 (d, 1H), 3.91 (s, 3H), 3.54 (m, 1H), 3.48 (s, 2H), 3.07 (m, 1H), 1.49 (d, 6H), 1.13 (d, 6H).

[0984] LCMS: m/z 475 (M+H).sup.+ (ES.sup.+); 473 (MH).sup. (ES.sup.).

Example 24: 2-(4-Fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)-N-((1-isopropyl-1H-pyrazol-3-yl)sulfonyl)acetamide, potassium salt

[0985] ##STR00275##

[0986] 1-Isopropyl-1H-pyrazole-3-sulfonamide (79 mg, 0.42 mmol) and triethylamine (0.12 mL, 0.84 mmol) were stirred in DCM (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetyl chloride (Intermediate A5) (61 mg, 0.21 mmol) in DCM (1 mL) was added dropwise. The reaction mixture was stirred overnight at room temperature and then concentrated. The residue was dissolved in DMSO (0.5 mL) and KOtBu (47 mg, 0.42 mmol) was added. The mixture was filtered over cotton wool and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford crude product (7 mg). The crude product was subjected to preparative HPLC (see Experimental Methods, Purification Method 2) to afford the title compound (2 mg, 2%) as a white solid.

[0987] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.53 (d, 1H), 8.43 (s, 1H), 7.73 (m, 2H), 7.49-7.36 (m, 1H), 7.08 (d, 1H), 6.79 (d, 1H), 6.72 (d, 1H), 3.52 (m, 1H), 3.50 (s, 2H), 2.97 (m, 1H), 1.56-1.44 (m, 6H), 1.14 (d, 6H).

[0988] LCMS: m/z 445 (M+H).sup.+ (ES.sup.+); 443 (MH).sup. (ES.sup.).

Example 25:2-(4-Fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)-N-((4-(2-hydroxypropan-2-yl)thiophen-2-yl)sulfonyl)acetamide

[0989] ##STR00276##

[0990] 4-(2-Hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate P14) (93 mg, 0.42 mmol) and triethylamine (0.12 mL, 0.84 mmol) were stirred in DCM (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetyl chloride (Intermediate A5) (61 mg, 0.21 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature and then concentrated. The residue was dissolved in DMSO (0.5 mL). The mixture was filtered over cotton wool and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford crude product (6 mg). The crude product was subjected to preparative HPLC (see Experimental Methods, Purification Method 2) to afford the title compound (3 mg, 3%) as a white solid.

[0991] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.50 (d, 1H), 8.40 (s, 1H), 7.72 (d, 1H), 7.54 (s, 1H), 7.43-7.32 (m, 1H), 7.07 (dd, 1H), 6.78 (d, 1H), 3.45 (s, 3H), 3.0 (m, 1H), 1.52 (s, 6H), 1.14 (d, 6H).

[0992] LCMS: m/z 477 (M+H).sup.+ (ES.sup.+); 475 (MH).sup. (ES.sup.).

Example 26:2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((4-(2-hydroxypropan-2-yl)thiophen-2-yl)sulfonyl)acetamide

[0993] ##STR00277##

[0994] 4-(2-Hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate P14) (89 mg, 0.4 mmol) and triethylamine (0.11 mL, 0.8 mmol) were stirred in DCM (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride (Intermediate A4) (64 mg, 0.2 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature and then concentrated. The residue was subjected to preparative HPLC (see Experimental Methods, Purification Method 2) to afford the title compound (2 mg, 2%) as a white solid.

[0995] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.00 (d, 1H), 7.67 (d, 1H), 7.44 (s, 1H), 7.03 (d, 1H), 6.86 (d, 1H), 6.78-6.69 (m, 2H), 3.89 (s, 3H), 3.45 (s, 2H), 3.07 (m, 1H), 1.51 (s, 6H), 1.12 (d, 6H).

[0996] LCMS: m/z 507 (M+H).sup.+ (ES.sup.+); 505 (MH).sup. (ES.sup.).

Example 27: 2-(4-Fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)-N-((4-(2-hydroxypropan-2-yl)thiophen-2-yl)sulfonyl)acetamide, potassium salt

[0997] ##STR00278##

[0998] A solution of 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate P14) (46 mg, 0.21 mmol, 2 eq) and triethylamine (29 L, 0.21 mmol, 2 eq) in anhydrous dichloromethane (2.5 mL) was cooled in an ice bath. A solution of 2-(4-fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetyl chloride (Intermediate A6) (30 mg, 0.1 mmol, 1 eq) in anhydrous dichloromethane (2.5 mL) was added dropwise. After addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The crude product was suspended in tetrahydrofuran, and potassium tert-butoxide (23 mg, 0.21 mmol, 2 eq) was added. After stirring for 5 minutes, the suspension was concentrated in vacuo. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (12 mg, 0.023 mmol, 23%) as a white solid.

[0999] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.48-8.41 (m, 2H), 7.66 (d, J=1.7 Hz, 1H), 7.44 (d, 1H), 7.42-7.30 (m, 2H), 7.06 (dd, 1H), 6.76 (dd, 1H), 3.42 (s, 2H), 3.09-2.99 (m, 1H), 1.51 (s, 6H), 1.14 (d, 6H).

[1000] LCMS: m/z 478 (M+H).sup.+ (ES.sup.+).

Example 28: Ethyl 3-(N-(2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl) phenyl)acetyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylate

[1001] ##STR00279##

[1002] Ethyl 1-methyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (75 mg, 0.32 mmol) and triethylamine (0.067 mL, 0.48 mmol) were dissolved in DCM (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride (Intermediate A4) (51 mg, 0.16 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature and then concentrated. The residue was dissolved in DMSO (0.5 mL). The mixture was filtered over cotton wool and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (36 mg, 43%) as a white solid.

[1003] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.07 (dd, 1H), 7.18 (s, 1H), 7.02 (dd, 1H), 6.90 (dd, 1H), 6.77 (d, 1H), 6.76-6.68 (m, 1H), 4.36 (q, 2H), 4.17 (s, 3H), 3.89 (s, 3H), 3.46 (s, 2H), 3.07 (m, 1H), 1.36 (t, 3H), 1.14 (d, 6H).

[1004] LCMS: m/z 519 (M+H).sup.+ (ES.sup.+).

Example 29: N-((3,3-Dimethyl-1-oxo-1,3-dihydroisobenzofuran-5-yl) sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) acetamide

[1005] ##STR00280##

[1006] 3,3-Dimethyl-1-oxo-1,3-dihydroisobenzofuran-5-sulfonamide (82 mg, 0.34 mmol) and triethylamine (0.047 mL, 0.34 mmol) were dissolved in DCM (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride (Intermediate A4) (55 mg, 0.17 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature and then concentrated. The residue was partitioned between water and DCM, filtered and the organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (15 mg, 17%) as a white solid.

[1007] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.31 (s, m, 1H), 8.27 (m, 1H), 8.04 (dd, 1H), 7.68 (dd, 1H), 6.97 (dd, 1H), 6.84 (dd, 1H), 6.76-6.60 (m, 2H), 3.90 (s, 3H), 3.42 (s, 2H), 2.94 (q, 1H), 1.67 (s, 6H), 1.03 (d, 6H).

[1008] LCMS: m/z 527 (M+H).sup.+ (ES.sup.+); 525 (MH).sup. (ES.sup.).

Example 30: N-((3-Cyanophenyl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide

[1009] ##STR00281##

[1010] 3-Cyanobenzenesulfonamide (62 mg, 0.34 mmol) and triethylamine (0.047 mL, 0.34 mmol) were dissolved in DCM (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride (Intermediate A4) (55 mg, 0.17 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature and partitioned between water and DCM. The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (18 mg, 23%) as a white solid.

[1011] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.23 (m, 1H), 8.17 (m, 1H), 8.03 (dd, 1H), 7.86 (dt, 1H), 7.65 (t, 1H), 7.00 (dd, 1H), 6.81 (dd, 1H), 6.76-6.65 (m, 2H), 3.90 (d, 3H), 3.43 (s, 2H), 3.04-2.85 (m, 1H), 1.09 (d, 6H).

[1012] LCMS: m/z 468 (M+H).sup.+ (ES.sup.+); 466 (MH).sup. (ES.sup.).

Example 31: N-((4-((Dimethylamino)methyl)phenyl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide, potassium salt

[1013] ##STR00282##

[1014] 4-((Dimethylamino)methyl)benzenesulfonamide (55 mg, 0.26 mmol) and KO.sup.tBu (58 mg, 0.51 mmol) were dissolved in THF (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride (Intermediate A4) (55 mg, 0.17 mmol) in THF (1 mL) was added dropwise. The mixture was stirred overnight at room temperature and concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (28 mg, 33%) as a white solid.

[1015] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.02 (d, 1H), 7.95 (d, 2H), 7.56-7.46 (m, 2H), 7.00 (dd, 1H), 6.82 (dd, 1H), 6.71 (dd, 2H), 4.01 (s, 2H), 3.91 (s, 3H), 3.44 (s, 2H), 3.11-2.94 (m, 1H), 2.59 (s, 6H), 1.09 (d, 6H).

[1016] LCMS: m/z 500 (M+H).sup.+ (ES.sup.+); 498 (MH).sup. (ES.sup.).

Example 32: N-((3-(Cyanomethyl)phenyl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide

[1017] ##STR00283##

[1018] 3-(Cyanomethyl)benzenesulfonamide (67 mg, 0.34 mmol) and triethylamine (0.047 mL, 0.34 mmol) were dissolved in DCM (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride (Intermediate A4) (55 mg, 0.17 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature and partitioned between water and DCM. The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (8 mg, 10%) as a white solid.

[1019] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 7.98 (d, 2H), 7.92 (dt, 1H), 7.69-7.52 (m, 2H), 7.03 (dd, 1H), 6.77-6.67 (m, 2H), 6.66-6.58 (m, 1H), 4.03 (s, 2H), 3.90 (s, 3H), 3.47 (s, 2H), 2.95-2.77 (m, 1H), 1.08 (d, 6H).

[1020] LCMS: m/z 482 (M+H).sup.+ (ES.sup.+); 480 (MH).sup. (ES.sup.).

Example 33: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((4-(2-hydroxypropan-2-yl)-2-methylphenyl)sulfonyl)acetamide

[1021] ##STR00284##

[1022] 4-(2-Hydroxypropan-2-yl)-2-methylbenzenesulfonamide (Intermediate P3) (73 mg, 0.32 mmol) and triethylamine (0.044 mL, 0.32 mmol) were dissolved in DCM (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride (Intermediate A4) (51 mg, 0.16 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature and partitioned between water and DCM. The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (8 mg, 10%) as a white solid.

[1023] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.04 (d, 1H), 7.92 (d, 1H), 7.38 (s, 1H), 7.33 (d, 1H), 6.98 (dd, 1H), 6.82 (dd, 1H), 6.74 (d, 1H), 6.69 (dd, 1H), 3.91 (s, 3H), 3.46 (s, 2H), 3.00 (m, 1H), 2.61 (s, 3H), 1.51 (s, 6H), 1.07 (d, 6H).

[1024] LCMS: m/z 515 (M+H).sup.+ (ES.sup.+); 513 (MH).sup. (ES.sup.).

Example 34: N-((3-Cyano-4-fluorophenyl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide

[1025] ##STR00285##

[1026] 3-Cyano-4-fluorobenzenesulfonamide (64 mg, 0.32 mmol) and triethylamine (0.044 mL, 0.32 mmol) were dissolved in DCM (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride (Intermediate A4) (51 mg, 0.16 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature and partitioned between water and DCM. The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (6 mg, 8%) as a white solid.

[1027] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.26 (dd, 1H), 8.21 (ddd, 1H), 8.05 (dd, 1H), 7.46 (t, 1H), 7.02 (dd, 1H), 6.83 (dd, 1H), 6.74-6.70 (m, 1H), 6.67 (dd, 1H), 3.91 (s, 3H), 3.43 (s, 2H), 2.97 (m, 1H), 1.10 (d, 6H).

[1028] LCMS: m/z 486 (M+H).sup.+ (ES.sup.+); 484 (MH).sup. (ES.sup.).

Example 35: N-((5-Cyano-2-methylphenyl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide

[1029] ##STR00286##

[1030] 5-Cyano-2-methylbenzenesulfonamide (64 mg, 0.32 mmol) and triethylamine (0.044 mL, 0.32 mmol) were dissolved in DCM (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride (Intermediate A4) (51 mg, 0.16 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature and partitioned between water and DCM. The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (24 mg, 31%) as a white solid.

[1031] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.27 (d, 1H), 8.05 (d, 1H), 7.71 (dd, 1H), 7.46 (d, 1H), 7.00 (dd, 1H), 6.81 (dd, 1H), 6.74-6.64 (m, 2H), 3.91 (s, 3H), 3.46 (s, 2H), 3.03-2.90 (m, 1H), 2.66 (s, 3H), 1.09 (d, 6H).

[1032] LCMS: m/z 482 (M+H).sup.+ (ES.sup.+); 480 (MH).sup. (ES.sup.).

Example 36: N-((4-((Dimethylamino)methyl)phenyl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetamide

[1033] ##STR00287##

[1034] To a suspension of 4-((dimethylamino)methyl)benzenesulfonamide (44 mg, 0.2 mmol, 1 eq) in anhydrous tetrahydrofuran (2 mL) was added potassium tert-butoxide (23 mg, 0.2 mmol, 2 eq). The suspension was stirred for 30 minutes at room temperature and then cooled in an ice bath. To the suspension was added a solution of 2-(4-fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetyl chloride (Intermediate A6) (30 mg, 0.1 mmol, 1 eq) in anhydrous tetrahydrofuran (2 mL). After complete addition, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After stirring over the weekend, the reaction mixture was concentrated in vacuo. The crude product was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (4 mg, 8 mol, 8%).

[1035] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.49-8.39 (m, 2H), 7.95-7.86 (m, 2H), 7.45 (d, 2H), 7.37-7.28 (m, 2H), 7.02 (dd, 1H), 6.73 (dd, 1H), 3.70 (s, 2H), 3.40 (s, 2H), 3.13-2.95 (m, 1H), 2.36 (s, 6H), 1.09 (d, 6H).

[1036] LC-MS: m/z 503 (M+H).sup.+ (ES.sup.+).

Example 37: N-((4-Cyano-2-methylphenyl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide

[1037] ##STR00288##

[1038] 4-Cyano-2-methylbenzenesulfonamide (64 mg, 0.32 mmol) and DIPEA (0.056 mL, 0.32 mmol) were dissolved in DCM (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride (Intermediate A4) (51 mg, 0.16 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature and partitioned between water and DCM. The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (19 mg, 25%) as a white solid.

[1039] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.10 (d, 1H), 8.05 (dd, 1H), 7.63 (d, 1H), 7.59 (dd, 1H), 6.99 (dd, 1H), 6.82 (dd, 1H), 6.73-6.63 (m, 2H), 3.92 (s, 3H), 3.46 (s, 2H), 3.04-2.89 (m, 1H), 2.62 (s, 3H), 1.09 (d, 6H).

[1040] LCMS: m/z 482 (M+H).sup.+ (ES.sup.+); 480 (MH).sup. (ES.sup.).

Example 38:2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((3-(hydroxymethyl)phenyl)sulfonyl)acetamide, potassium salt

[1041] ##STR00289##

[1042] 3-(Hydroxymethyl)benzenesulfonamide (60 mg, 0.32 mmol) and DIPEA (0.056 mL, 0.32 mmol) were dissolved in DCM (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride (Intermediate A4) (51 mg, 0.16 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred for 2 hours at room temperature. Then EDC (31 mg, 0.16 mmol) and DMAP (20 mg, 0.16 mmol) were added and the mixture was stirred overnight. Water and DCM were added and the organic phase was separated and concentrated. The residue was dissolved in DMSO (0.5 mL) and KOtBu (54 mg, 0.48 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (7 mg, 9%) as a white solid.

[1043] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 7.99 (d, 1H), 7.92 (s, 1H), 7.80 (d, 1H), 7.45 (dt, 2H), 6.98 (dd, 1H), 6.82 (dd, 1H), 6.75 (s, 1H), 6.69 (dd, 1H), 4.64 (s, 2H), 3.88 (s, 3H), 3.42 (s, 2H), 3.06-2.93 (m, 1H), 1.08 (d, 6H).

[1044] LCMS: m/z 473 (M+H).sup.+ (ES.sup.+); 471 (MH).sup. (ES.sup.).

Example 39: Methyl 4-(N-(2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl)sulfamoyl)-3-methylbenzoate

[1045] ##STR00290##

[1046] Methyl 3-methyl-4-sulfamoylbenzoate (73 mg, 0.32 mmol) and DIPEA (0.056 mL, 0.32 mmol) were dissolved in DCM (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride (Intermediate A4) (51 mg, 0.16 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature. EDC (31 mg, 0.16 mmol) and DMAP (20 mg, 0.16 mmol) were added and the mixture was stirred overnight. Water and DCM were added and the organic phase was separated and concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (43 mg, 52%) as a white solid.

[1047] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.09-7.99 (m, 2H), 7.89 (s, 1H), 7.87-7.81 (m, 1H), 6.98 (dd, 1H), 6.81 (dd, 1H), 6.74-6.64 (m, 2H), 3.91 (d, 6H), 3.46 (s, 2H), 2.99 (dd, 1H), 2.64 (s, 3H), 1.08 (d, 6H).

[1048] LCMS: m/z 515 (M+H).sup.+ (ES.sup.+); 513 (MH).sup. (ES.sup.).

Example 40: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((4-(2-hydroxypropan-2-yl)furan-2-yl)sulfonyl)acetamide

[1049] ##STR00291##

[1050] A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (31 mg, 0.102 mmol), EDC (39 mg, 0.203 mmol), DMAP (25 mg, 0.205 mmol) and 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide (Intermediate P27) (21 mg, 0.102 mmol) in DMF (1.5 mL) was stirred for 16 hours at room temperature. The crude product was purified by acidic prep HPLC (see Experimental Methods, Purification Method 3) (20-50% MeCN in water) to afford the title compound (25 mg, 49%) as a white solid.

[1051] .sup.1H NMR (DMSO-d.sub.6) 12.46 (s, 1H), 8.15 (d, J=5.7 Hz, 1H), 7.88 (s, 1H), 7.29 (s, 1H), 7.21 (dd, J=10.5, 2.8 Hz, 1H), 6.89 (dd, J=8.8, 2.8 Hz, 1H), 6.66-6.61 (m, 2H), 5.15 (s, 1H), 3.90 (s, 3H), 3.52 (s, 2H), 2.81 (p, J=6.9 Hz, 1H), 1.38 (s, 6H), 1.08 (d, J=6.7 Hz, 6H).

[1052] LCMS m/z 491.3 (M+H).sup.+ (ES.sup.+).

Example 41:2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((1-phenylethyl)sulfonyl)acetamide

[1053] ##STR00292##

[1054] A solution of 1-phenylethanesulfonamide (18.52 mg, 0.100 mmol), 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (30.3 mg, 0.100 mmol), EDC (38.3 mg, 0.200 mmol) and DMAP (24.43 mg, 0.200 mmol) in DMF (1.4 mL) was shaken at room temperature for 16 hours in a 96-well plate at 900 rpm. The product was purified by acidic prep HPLC (see Experimental Methods, Purification Method 3) (40-70% MeCN in water) to afford the title compound (18.7 mg, 39%) as a white solid.

[1055] .sup.1H NMR (DMSO-d.sub.6) 11.66 (s, 1H), 8.22 (d, J=5.2 Hz, 1H), 7.43-7.30 (m, 5H), 7.26 (dd, J=10.5, 2.8 Hz, 1H), 6.93 (dd, J=8.9, 2.8 Hz, 1H), 6.86 (dd, J=5.2, 1.4 Hz, 1H), 6.74-6.69 (m, 1H), 4.73 (q, J=7.1 Hz, 1H), 3.89 (s, 3H), 3.51 (d, J=18.0 Hz, 1H), 3.40 (d, J=18.0 Hz, 1H), 2.93-2.83 (m, 1H), 1.64 (d, J=7.2 Hz, 3H), 1.22 (d, J=6.7 Hz, 3H), 1.17 (d, J=6.7 Hz, 3H).

[1056] LCMS m/z 471.6 (M+H).sup.+ (ES.sup.+).

Example 42: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((1-methyl-1H-pyrazol-4-yl)sulfonyl)acetamide

[1057] ##STR00293##

[1058] Prepared according to the general procedure of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((1-phenylethyl)sulfonyl)acetamide (Example 41) from 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) and 1-methyl-H-pyrazole-4-sulfonamide to afford the title compound (16 mg, 35%) as a white solid.

[1059] .sup.1H NMR (DMSO-d.sub.6) 12.10 (s, 1H), 8.41 (s, 1H), 8.06 (d, J=5.2 Hz, 1H), 7.82 (s, 1H), 7.19 (dd, J=10.5, 2.8 Hz, 1H), 6.87 (dd, J=8.9, 2.8 Hz, 1H), 6.64 (dd, J=5.2, 1.4 Hz, 1H), 6.58 (s, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.46 (s, 2H), 2.81-2.72 (m, 1H), 1.04 (d, J=6.7 Hz, 6H).

[1060] LCMS m/z 447.2 (M+H).sup.+ (ES.sup.+).

Example 43: N-((4-Acetylphenyl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide

[1061] ##STR00294##

[1062] Prepared according to the general procedure of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((1-phenylethyl)sulfonyl)acetamide (Example 41) from 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) and 4-acetylbenzenesulfonamide to afford the title compound (24 mg, 49%) as a white solid.

[1063] .sup.1H NMR (DMSO-d.sub.6) 12.42 (s, 1H), 8.22-8.10 (m, 2H), 8.05 (d, J=5.2 Hz, 1H), 8.04-7.92 (m, 2H), 7.14 (dd, J=10.5, 2.8 Hz, 1H), 6.83 (dd, J=8.9, 2.8 Hz, 1H), 6.63-6.49 (m, 2H), 3.87 (s, 3H), 3.48 (s, 2H), 2.84-2.68 (m, 1H). 2.64 (s, 3H), 0.99 (d, J=6.7 Hz, 6H).

[1064] LCMS m/z 485.3 (M+H).sup.+ (ES.sup.+).

Example 44: 2-(5-(2-Cyanopyridin-4-yl)-2,3-dihydro-H-inden-4-yl)-N-((1-cyclopropyl-1H-pyrazol-3-yl)sulfonyl)acetamide

[1065] ##STR00295##

[1066] To a solution of 1-cyclopropyl-1H-pyrazole-3-sulfonamide (Intermediate P5) (29 mg, 0.15 mmol, 1.3 eq) in anhydrous dichloromethane (2 mL) was added triethylamine (34 L, 0.24 mmol, 2 eq). The solution was cooled in an ice bath. Then a solution of 2-(5-(2-cyanopyridin-4-yl)-2,3-dihydro-H-inden-4-yl)acetyl chloride (Intermediate A3) (35 mg, 0.12 mmol, 1 eq) in anhydrous dichloromethane (2 mL) was added dropwise. After complete addition, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature. After stirring over the weekend, the reaction mixture was concentrated in vacuo. The crude product was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (1.4 mg, 3.1 mol, 2%).

[1067] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.63 (dd, 1H), 7.85 (dd, 1H), 7.70-7.55 (m, 2H), 7.18 (d, 1H), 7.02 (d, 1H), 6.62 (d, 1H), 3.78-3.64 (m, 1H), 3.46 (s, 2H), 2.95 (t, 2H), 2.84 (t, 2H), 2.08 (p, 2H), 1.19-0.94 (m, 4H).

[1068] LCMS: m/z 448 (M+H).sup.+ (ES.sup.+).

Example 45: N-((1-Cyclopropyl-1H-pyrazol-3-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetamide, potassium salt

[1069] ##STR00296##

[1070] To a suspension of 1-cyclopropyl-1H-pyrazole-3-sulfonamide (Intermediate P5) (20 mg, 0.1 mmol, 1 eq) in anhydrous tetrahydrofuran (2 mL) was added potassium tert-butoxide (12 mg, 0.1 mmol, 1 eq). The suspension was stirred for 30 minutes at room temperature and then cooled in an ice bath. To the suspension was added a solution of 2-(4-fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetyl chloride (Intermediate A6) (30 mg, 0.1 mmol, 1 eq) in anhydrous tetrahydrofuran (2 mL). After complete addition, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After stirring over the weekend, the reaction mixture was concentrated in vacuo. The crude product was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (1 mg, 2 mol, 2%).

[1071] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.51 (d, 2H), 7.71 (s, 1H), 7.35 (d, 2H), 7.07 (d, 1H), 6.77-6.79 (m, 1H), 6.67 (s, 1H), 4.56 (s, 2H), 3.54 (m, 1H), 3.10-3.00 (m, 1H), 1.31 (m, 2H) 1.15 (d, 6H), 1.07 (s, 2H).

[1072] LC-MS: m/z 443 (M+H).sup.+ (ES.sup.+).

Example 46: N-((1-Cyclopropyl-1H-imidazol-4-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide

[1073] ##STR00297##

[1074] To a mixture of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (37 mg, 122.85 mol, 1 eq), EDC (47 mg, 245.70 mol, 2 eq) and DMAP (23 mg, 184.28 mol, 1.5 eq) in DMF (1 mL) was added 1-cyclopropyl-1H-imidazole-4-sulfonamide (Intermediate P4) (23 mg, 122.85 mol, 1 eq). The reaction mixture was stirred at 20 C. for 24 hours, and then filtered. The filtrate was purified by reversed phase flash chromatography (0.1% TFA in water-MeCN) and then purified by prep-HPLC (column: Xtimate C18, 15 mm*25 mm*5 m; mobile phase [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 14%-44%, min) to give the title compound (7.72 mg, 13% yield, 100% purity on LCMS) as a white solid.

[1075] .sup.1H NMR (400 MHz, CDCl.sub.3) 10.31 (br s, 1H), 8.16 (d, 1H), 7.75-7.73 (m, 1H), 7.58-7.56 (m, 1H), 7.01 (dd, 1H), 6.74-6.72 (m, 2H), 6.60 (s, 1H), 3.99 (s, 3H), 3.60 (s, 2H), 3.42-3.38 (m, 1H), 2.88-2.83 (m, 1H) and 1.15-1.02 (m, 10H).

[1076] LCMS: m/z 473.1 (M+H).sup.+ (ES.sup.+).

Example 47: N-((1-Cyclopropyl-1H-pyrazol-3-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide

[1077] ##STR00298##

[1078] To a solution A of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (50 mg, 164.84 mol, 1 eq) in DMF (0.5 mL) was added CDI (40 mg, 247.26 mol, 1.5 eq) at 25 C. Then the solution A was stirred at 25 C. for 30 minutes. To another solution B of 1-cyclopropyl-H-pyrazole-3-sulfonamide (Intermediate P5) (40 mg, 214.29 mol, 1.3 eq) in DMF (0.5 mL) was added NaH (9 mg, 247.26 mol, 60 wt % in mineral oil, 1.5 eq) at 0 C. The solution B was stirred at 0 C. for 30 minutes. Then the solution A was added dropwise into solution B. The reaction mixture was stirred at 25 C. for 1 hour, and then purified directly by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (37.23 mg, 48% yield, 100% purity on LCMS) as a white solid.

[1079] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.00 (d, 1H), 7.43 (d, 1H), 6.98 (dd, 1H), 6.72-6.69 (m, 3H), 6.60 (d, 1H), 3.87 (s, 3H), 3.53 (s, 2H), 3.51-3.42 (m, 1H), 2.92-2.88 (m, 1H), 1.04 (d, 6H), 1.01-0.98 (m, 2H) and 0.82-0.67 (m, 2H).

[1080] LCMS: m/z 473.3 (M+H).sup.+ (ES.sup.+).

Example 48: N-((2-Cyclopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetamide

[1081] ##STR00299##

[1082] To a mixture of 2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid (Intermediate A2, Step F, non salt form) (75 mg, 265.66 mol, 1 eq) and DMAP (64 mg, 531.33 mol, 2 eq) in DMF (3.5 mL) was added EDC (101 mg, 531.33 mol, 2 eq). The mixture was stirred at 25 C. for 10 minutes. Then 2-cyclopropyl-2H-1,2,3-triazole-4-sulfonamide (Intermediate P6) (50 mg, 265.66 mol, 1 eq) was added. The reaction mixture was stirred at 25 C. for 3 hours, and then concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.1% NH.sub.3.H.sub.2O-MeCN) and then further purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase [A: water (0.04% NH.sub.3.H.sub.2O+10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 20%-52%,43 min) to give the title compound (36.33 mg, 45% yield, 100% purity on LCMS) as a white solid.

[1083] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.15 (d, 1H), 8.06 (s, 1H), 7.25 (d, 1H), 7.06 (d, 1H), 6.69 (dd, 1H), 6.57 (s, 1H), 4.16-4.11 (m, 1H), 3.96 (s, 3H), 3.59 (s, 2H), 3.00 (t, 2H), 2.78 (t, 2H), 2.15-2.09 (m, 2H), 1.42-1.39 (m, 2H) and 1.19-1.17 (m, 2H).

[1084] LCMS: m/z 454.3 (M+H).sup.+ (ES.sup.+).

Example 49: N-((1-Cyclopropyl-1H-imidazol-4-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetamide

[1085] ##STR00300##

[1086] To a solution A of 1-cyclopropyl-1H-imidazole-4-sulfonamide (Intermediate P4) (40 mg, 213.65 mol, 1 eq) in DMF (1 mL) was added NaH (12 mg, 320.48 mol, 60 wt % in mineral oil, 1.5 eq) in one portion at 0 C. Then the mixture A was stirred at 0 C. for 0.5 hour. To a solution B of 2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetic acid (Intermediate A5, Step J) (58 mg, 213.65 mol, 1 eq) in DMF (1 mL) was added CDI (41 mg, 256.38 mol, 1.2 eq) in one portion at 0 C. The mixture B was stirred at 0 C. for 0.5 hour. Then the mixture A was added dropwise to the mixture B at 0 C. The reaction mixture was stirred at 25 C. for 16 hours, and then purified by prep-HPLC (column: Phenomenex Synergi C18, 150 mm*25 mm*10 m; mobile phase [A: water (0.1% TFA); B: MeCN]; B %: 21%-45%, 8 min) to give the title compound (6.61 mg, 5% yield, 100% purity on LCMS, TFA salt) as a white solid.

[1087] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.91 (s, 1H), 8.46 (s, 1H), 8.04 (d, 1H), 7.85-7.81 (m, 2H), 7.70 (s, 1H), 7.11 (dd, 1H), 6.72 (dd, 1H), 3.61 (s, 2H), 3.47-3.44 (m, 1H), 2.98-2.95 (m, 1H), 1.15 (d, 6H), 1.11-1.08 (m, 2H) and 1.04-1.02 (m, 2H).

[1088] LCMS: m/z 443.0 (M+H).sup.+ (ES.sup.+).

Example 50: 2-(2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)-N-((2-cyclopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)acetamide

[1089] ##STR00301##

[1090] To a mixture of 2-cyclopropyl-2H-1,2,3-triazole-4-sulfonamide (Intermediate P6) (22 mg, 119.55 mol, 1.5 eq) and 2-(2-(2-cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid (Intermediate A7) (23 mg, 79.70 mol, 1 eq) in DMF (0.5 mL) was added DMAP (10 mg, 87.67 mol, 1.1 eq) and EDC (30 mg, 159.40 mol, 2 eq). The reaction mixture was stirred at 25 C. for 1 hour, and then purified by prep-HPLC (column: Phenomenex Synergi C18, 150 mm*25 mm*10 m; mobile phase [A: water (0.1% TFA); B: MeCN]; B %: 45%-75%, 10 min) to give the title compound (6.85 mg, 15% yield, 100% purity on LCMS, TFA salt) as a yellow solid.

[1091] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.68 (d, 1H), 8.09 (s, 1H), 7.75 (d, 1H), 7.45 (dd, 1H), 7.17 (dd, 1H), 6.86 (dd, 1H), 4.27-4.21 (m, 1H), 3.56 (s, 2H), 2.92-2.86 (m, 1H), 1.37-1.35 (m, 2H), 1.22-1.20 (m, 2H) and 1.15 (d, 6H).

[1092] LCMS: m/z 469.2 (M+H).sup.+ (ES.sup.+).

Example 51: 2-(5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)-N-((2-cyclopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)acetamide

Step A: 4-(4-(2-(2-Cyclopropyl-2H-1,2,3-triazole-4-sulfonamido)-2-oxoethyl)-2,3-dihydro-1H-inden-5-yl)picolinamide

[1093] ##STR00302##

[1094] To a solution of 2-(5-(2-carbamoylpyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid (Intermediate A8) (80 mg, 269.98 mol, 1 eq) in DMF (1 mL) was added EDC (104 mg, 539.96 mol, 2 eq), DMAP (66 mg, 539.96 mol, 2 eq) and 2-cyclopropyl-2H-1,2,3-triazole-4-sulfonamide (Intermediate P6) (61 mg, 323.97 mol, 1.2 eq). The reaction mixture was stirred at 25 C. for 2 hours, and then purified directly by reversed phase flash chromatography (0.1% TFA in water-MeCN) to give the title compound (80 mg, 64%) as a yellow solid.

[1095] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.6 (d, 1H), 8.07 (s, 1H), 8.01 (s, 1H), 7.37 (d, 1H), 7.26 (d, 1H), 7.05 (d, 1H), 4.28-4.22 (m, 1H), 3.59 (s, 2H), 2.99 (t, 2H), 2.75 (t, 2H), 2.15-2.08 (m, 2H), 1.38-1.34 (m, 2H) and 1.24-1.19 (m, 2H).

[1096] LCMS: m/z 467.0 (M+H).sup.+ (ES.sup.+).

Step B: 2-(5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)-N-((2-cyclopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)acetamide

[1097] ##STR00303##

[1098] To a solution of 4-(4-(2-(2-cyclopropyl-2H-1,2,3-triazole-4-sulfonamido)-2-oxoethyl)-2,3-dihydro-1H-inden-5-yl)picolinamide (30 mg, 64.31 mol, 1 eq) in DCM (5 mL) was added TFAA (27 mg, 128.61 mol, 2 eq) and TEA (26 mg, 257.23 mol, 4 eq) at 0 C. The reaction mixture was stirred at 25 C. for 16 hours, and then poured into saturated aqueous NaHCO.sub.3 solution (10 mL) and extracted with DCM (310 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Luna C18, 150 mm*25 mm*5 m; mobile phase [A: water (0.075% TFA); B: MeCN]; B %: 45%-75%, 9 min) to give the title compound (0.23 mg, 1% yield, 97% purity on LCMS) as a white solid.

[1099] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.66 (d, 1H), 7.95 (s, 1H), 7.85 (s, 1H), 7.60 (dd, 1H), 7.23 (d, 1H), 7.05 (d, 1H), 4.21-4.16 (m, 1H), 3.51 (s, 2H), 3.00 (t, 2H), 2.83 (t, 2H), 2.15-2.08 (m, 2H), 1.37-1.33 (m, 2H) and 1.20-1.16 (m, 2H).

[1100] LCMS: m/z 449.0 (M+H).sup.+ (ES.sup.+).

Example 52: 2-(2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)-N-((1-cyclopropyl-1H-pyrazol-4-yl)sulfonyl)acetamide

[1101] ##STR00304##

[1102] To a mixture of 2-(2-(2-cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid (Intermediate A7) (45 mg, 150.85 mol, 1 eq) in DMF (2 mL) was added EDC (43 mg, 226.27 mol, 1.5 eq) and DMAP (27 mg, 226.27 mol, 1.5 eq) in one portion. The reaction mixture was stirred at 25 C. for 0.5 hour. Then 1-cyclopropyl-H-pyrazole-4-sulfonamide (Intermediate P7) (28 mg, 150.85 mol, 1 eq) was added. The resulting reaction mixture was stirred for 1.5 hours, and then directly purified by prep-HPLC (column: Boston Prime C18, 150 mm*30 mm*5 m; mobile phase [A: water (0.1% TFA); B: MeCN]; B %: 42%-72%, 9 min) to give the title compound (2.77 mg, 3% yield, 100% purity on LCMS, TFA salt) as a yellow solid.

[1103] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.63 (d, 1H), 8.29 (s, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.45 (dd, 1H), 7.18 (dd, 1H), 6.87 (dd, 1H), 3.80-3.76 (m, 1H), 3.50 (s, 2H), 2.88-2.86 (m, 1H) and 1.15-1.07 (m, 10H).

[1104] LCMS: m/z 468.2 (M+H).sup.+ (ES.sup.+).

Example 53: N-((1-Cyclopropyl-1H-pyrazol-4-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-2-hydroxyacetamide

Step A: 2-(1-Cyclopropyl-1H-pyrazole-4-sulfonamido)-1-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-2-oxoethyl acetate

[1105] ##STR00305##

[1106] To a mixture of 2-acetoxy-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A9) (15 mg, 41.51 mol, 1 eq) in DMF (1 mL) was added CDI (10 mg, 62.26 mol, 1.5 eq). The mixture was stirred at 20 C. for 0.5 hour. Then the above solution was added into a solution of 1-cyclopropyl-H-pyrazole-4-sulfonamide (Intermediate P7) (11 mg, 62.26 mol, 1.5 eq) and NaH (2 mg, 62.26 mol, 60 wt % in mineral oil, 1.5 eq) in DMF (1 mL) which had been stirred for 0.5 hour at 20 C. The reaction mixture was stirred at 20 C. for another 1 hour, and then quenched with water (0.2 mL) and filtered. The filtrate was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 2%-32%, 10 min) to give the title compound (2.3 mg, 10%) as a yellow solid.

[1107] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.11 (d, 1H), 8.09 (s, 1H), 7.77 (s, 1H), 7.07 (dd, 2H), 6.77 (dd, 1H), 6.20 (s, 1H), 4.88 (s, 1H), 3.94 (s, 3H), 3.69-3.66 (m, 1H), 3.31-3.26 (m, 1H), 2.01 (s, 3H), 1.19 (d, 3H), 1.10-1.04 (m, 4H) and 0.89 (d, 3H).

[1108] LCMS: m/z 531.1 (M+H).sup.+ (ES.sup.+).

Step B: N-((1-Cyclopropyl-1H-pyrazol-4-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-2-hydroxyacetamide

[1109] ##STR00306##

[1110] To a mixture of 2-(1-cyclopropyl-1H-pyrazole-4-sulfonamido)-1-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-2-oxoethyl acetate (4 mg, 8.67 mol, 1 eq) in MeOH (1 mL) was added K.sub.2CO.sub.3 (2 mg, 17.34 mol, 2 eq). The reaction mixture was stirred at 20 C. for 12 hours, and then filtered. The filtrate was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 10%-50%, 10 min) to give the title compound (2.42 mg, 57% yield, 99% purity on LCMS) as a white solid.

[1111] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.22 (s, 1H), 8.13 (d, 1H), 7.83 (s, 1H), 7.07 (dd, 1H), 7.02 (s, 1H), 6.90 (s, 1H), 6.77 (dd, 1H), 5.08 (s, 1H), 3.93 (s, 3H), 3.72-3.69 (m, 1H), 3.05-3.03 (m, 1H), 1.18 (d, 3H), 1.11-1.07 (m, 4H) and 0.77 (d, 3H).

[1112] LCMS: m/z 489.4 (M+H).sup.+ (ES.sup.+).

Example 54: N-((1-Cyclopropyl-1H-pyrazol-4-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetamide

[1113] ##STR00307##

[1114] To the mixture of 2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetic acid (Intermediate A5, Step J) (102 mg, 373.89 mol, 1 eq), EDC (143 mg, 747.79 mol, 2 eq) and DMAP (68 mg, 560.84 mol, 1.5 eq) in DMF (3 mL) was added 1-cyclopropyl-1H-pyrazole-4-sulfonamide (Intermediate P7) (70 mg, 373.89 mol, 1 eq). The reaction mixture was stirred at 20 C. for 1 hour, and then purified directly by reversed phase flash chromatography (0.1% TFA in water-MeCN) and then further purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 17%-47%, 10 min) to give the title compound (7.86 mg, 5% yield, 100% purity on LCMS) as a white solid.

[1115] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.10 (br s, 1H), 8.60 (dd, 1H), 8.41-8.39 (m, 2H), 7.77 (s, 1H), 7.53 (dd, 1H), 7.35 (dd, 1H), 7.18 (dd, 1H), 6.91 (dd, 1H), 3.89-3.83 (m, 1H), 3.43 (s, 2H), 2.84-2.81 (m, 1H) and 1.11-0.99 (m, 10H).

[1116] LCMS: m/z 443.3 (M+H).sup.+ (ES.sup.+).

Example 55: 2-(5-(2-Methoxypyridin-4-yl)-2,3-dihydro-H-inden-4-yl)-N(N-methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)acetamide, potassium salt

[1117] ##STR00308##

[1118] To a suspension of N-methyl-N-(1-methylpyrrolidin-3-yl)sulfamide (Intermediate P8) (76 mg, 0.39 mmol, 2.5 eq) in anhydrous tetrahydrofuran (2 mL) was added potassium tert-butoxide (47 mg, 0.42 mmol, 2.6 eq). The suspension was stirred for 30 minutes at room temperature. A solution of 2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetyl chloride (Intermediate A2) (48 mg, 0.16 mmol, 1 eq) in anhydrous tetrahydrofuran (2 mL) was added. After stirring over the weekend at room temperature, the reaction mixture was concentrated in vacuo. The crude product was subjected to preparative HPLC (see Experimental Methods, Purification Method 2) to afford the title compound (2 mg, 4 mol, 3%).

[1119] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.11 (d, 1H), 7.17 (d, 1H), 7.07-6.93 (m, 2H), 6.83 (s, 1H), 4.57 (s, 1H), 3.92 (s, 3H), 3.45 (s, 2H), 3.03-2.80 (m, 8H), 2.74 (d, 3H), 2.46 (s, 3H), 2.44-2.30 (m, 1H), 2.16-2.02 (m, 3H).

[1120] LCMS: m/z 459 (M+H).sup.+ (ES.sup.+).

Example 56: N-((3-(Diethylamino)propyl)sulfonyl)-2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetamide

[1121] ##STR00309##

[1122] To a suspension of 3-(diethylamino)propane-1-sulfonamide (Intermediate P9) (54 mg, 0.28 mmol, 2 eq) in anhydrous tetrahydrofuran (2 mL) was added potassium tert-butoxide (33 mg, 0.29 mmol, 2.1 eq). The suspension was stirred for 30 minutes at room temperature and then cooled in an ice bath. A solution of 2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetyl chloride (Intermediate A2) (42 mg, 0.14 mmol, 1 eq) in anhydrous tetrahydrofuran (2 mL) was added. After complete addition, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After stirring over the weekend, the reaction mixture was concentrated in vacuo. The crude product was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (5 mg, 10 mol, 7%).

[1123] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.10 (d, 1H), 7.15 (d, 1H), 7.02-6.95 (m, 2H), 6.86-6.82 (m, 1H), 3.96-3.88 (m, 3H), 3.50 (s, 2H), 3.31-3.24 (m, 4H), 3.18 (q, 4H), 2.94 (dt, 4H), 2.11 (h, 4H), 1.28 (t, 6H).

[1124] LCMS: m/z 460 (M+H).sup.+ (ES.sup.+).

Example 57: N-((3-(Diethylamino)propyl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide, potassium salt

[1125] ##STR00310##

[1126] 3-(Diethylamino)propane-1-sulfonamide (Intermediate P9) (78 mg, 0.4 mmol) and KO.sup.tBu (45 mg, 0.4 mmol) were stirred in THF (6 mL) for 45 minutes. A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride (Intermediate A4) (64 mg, 0.2 mmol) in THF (1 mL) was added dropwise. The mixture was stirred overnight at room temperature and then concentrated. The residue was dissolved in DMSO (0.5 mL). The mixture was filtered over cotton wool and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (11 mg, 11%) as a white solid.

[1127] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.13 (dd, 1H), 7.07 (dd, 1H), 6.98 (dd, 1H), 6.84 (dd, 1H), 6.76 (dd, 1H), 3.93 (s, 3H), 3.48 (s, 2H), 3.21 (dd, 2H), 3.14 (m, 1H), 2.87 (m, 4H), 2.71-2.55 (m, 2H), 2.06-1.89 (m, 2H), 1.24 (d, 6H), 1.11 (t, 6H).

[1128] LCMS: m/z 480 (M+H).sup.+ (ES.sup.+); 478 (MH).sup. (ES.sup.).

Example 58: 3-(N-(2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl) phenyl)acetyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, potassium salt

[1129] ##STR00311##

[1130] N,N,1-Trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P11) (93 mg, 0.4 mmol) and Et.sub.3N (0.11 mL, 0.8 mmol) were stirred in DCM (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride (Intermediate A4) (64 mg, 0.2 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature and then concentrated. The residue was dissolved in DMSO (0.5 mL) and KO.sup.tBu (45 mg, 0.4 mmol) was added. The mixture was filtered over cotton wool and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (8 mg, 8%) as a white solid.

[1131] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.07 (dd, 1H), 7.02 (dd, 1H), 6.90 (dd, 1H), 6.84 (s, 1H), 6.78 (dd, 1H), 6.72 (dd, 1H), 3.92 (d, 6H), 3.47 (s, 2H), 3.14 (m, 1H), 3.13 (dd, 6H), 1.14 (d, 6H).

[1132] LCMS: m/z 518 (M+H).sup.+ (ES.sup.+).

Example 59: 3-(N-(2-(4-Fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetyl) sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide

[1133] ##STR00312##

[1134] N,N,1-Trimethyl-3-sulfamoyl-H-pyrazole-5-carboxamide (Intermediate P11) (84 mg, 0.36 mmol) and Et.sub.3N (0.1 mL, 0.72 mmol) were stirred in DCM (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetyl chloride (Intermediate A5) (53 mg, 0.18 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature and then concentrated. The residue was dissolved in DMSO (0.5 mL). The mixture was filtered over cotton wool and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford crude product (10 mg). The crude product was subjected to preparative HPLC (see Experimental Methods, Purification Method 2) to afford the title compound (4 mg, 5%) as a white solid.

[1135] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.53 (d, 1H), 8.43 (s, 1H), 7.75 (d, 1H), 7.44 (dd, 1H), 7.07 (dd, 1H), 6.92 (s, 1H), 6.78 (dd, 1H), 3.97 (s, 3H), 3.49 (s, 2H), 3.10 (d, 6H), 3.08 (m, 1H), 1.16 (d, 6H).

[1136] LCMS: m/z 488 (M+H).sup.+ (ES.sup.+); 486 (MH).sup. (ES.sup.).

Example 60: 3-(N-(2-(4-Fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetyl) sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide, potassium salt

[1137] ##STR00313##

[1138] To a solution of N,N,1-trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P11) (48 mg, 0.2 mmol, 2 eq) and triethylamine (29 L, 0.2 mmol, 2 eq) in anhydrous dichloromethane (2.5 mL) cooled in an ice bath was added dropwise a solution of 2-(4-fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetyl chloride (Intermediate A6) (30 mg, 0.1 mmol, 1 eq) in anhydrous dichloromethane (2.5 mL). After complete addition, the ice bath was removed and the reaction mixture was stirred at room temperature. After 2 hours, the reaction mixture was concentrated in vacuo. The crude product was suspended in tetrahydrofuran, then potassium tert-butoxide (23 mg, 0.2 mmol, 2 eq) was added. After stirring for 5 minutes, the suspension was concentrated in vacuo. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (7.6 mg, 0.014 mmol, 14%) as a white solid.

[1139] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.55-8.44 (m, 2H), 7.43-7.30 (m, 2H), 7.06 (dd, 1H), 6.84 (s, 1H), 6.76 (dd, 1H), 3.95 (s, 3H), 3.44 (s, 2H), 3.36-3.33 (m, 1H), 3.10 (d, 6H), 1.15 (d, 6H).

[1140] LCMS: m/z 489 (M+H).sup.+ (ES.sup.+).

Example 61: N-((1-(1-(Dimethylamino)-2-methylpropan-2-yl)-1H-pyrazol-3-yl) sulfonyl)-2-(4-fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetamide, potassium salt

[1141] ##STR00314##

[1142] To a suspension of 1-(1-(dimethylamino)-2-methylpropan-2-yl)-1H-pyrazole-3-sulfonamide (51 mg, 0.2 mmol, 2 eq) in anhydrous tetrahydrofuran (2 mL) was added potassium tert-butoxide (23 mg, 0.2 mmol, 2 eq). The suspension was stirred for 30 minutes at room temperature and then cooled in an ice bath. A solution of 2-(4-fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetyl chloride (Intermediate A6) (30 mg, 0.1 mmol, 1 eq) in anhydrous tetrahydrofuran (2 mL) was added. After complete addition, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After stirring over the weekend, the reaction mixture was concentrated in vacuo. The crude product was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (2 mg, 4 mol, 4%).

[1143] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.53-8.47 (m, 2H), 7.74 (d, 1H), 7.46-7.37 (m, 2H), 7.05 (dd, 1H), 6.75 (dd, 1H), 6.63 (d, 1H), 3.43 (s, 2H), 3.19-3.11 (m, 1H), 2.81 (s, 2H), 2.09 (s, 6H), 1.59 (s, 6H), 1.17 (d, 6H).

[1144] LC-MS: m/z 503 (M+H).sup.+ (ES.sup.+).

Example 62: N-((5-((Dimethylamino)methyl)-1-methyl-1H-pyrazol-3-yl) sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) acetamide, potassium salt

[1145] ##STR00315##

[1146] 5-((Dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P10) (70 mg, 0.32 mmol) and KO.sup.tBu (54 mg, 0.48 mmol) were stirred in THF (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride (Intermediate A4) (51 mg, 0.16 mmol) in THF (1 mL) was added dropwise. The mixture was stirred overnight at room temperature and concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (24 mg, 30%) as a white solid.

[1147] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.06 (dd, 1H), 7.02 (dd, 1H), 6.91 (dd, 1H), 6.79 (dd, 1H), 6.72 (dd, 1H), 6.55 (s, 1H), 3.90 (d, 6H), 3.47 (d, 4H), 3.17-3.02 (m, 1H), 2.24 (s, 6H), 1.14 (d, 6H).

[1148] LCMS: m/z 504 (M+H).sup.+ (ES.sup.+); 502 (MH).sup. (ES.sup.).

Example 63: 2-(5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)-N-((1-isopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazol-3-yl)sulfonyl)acetamide, potassium salt

[1149] ##STR00316##

[1150] To a solution of 1-isopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P13) (49 mg, 0.18 mmol, 1.8 eq) in anhydrous tetrahydrofuran (2 mL) was added potassium tert-butoxide (20 mg, 0.18 mmol, 1.8 eq). The suspension was cooled in an ice bath. A solution of 2-(5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetyl chloride (Intermediate A3) (30 mg, 0.10 mmol, 1 eq) in anhydrous tetrahydrofuran (2 mL) was added dropwise. After complete addition, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature. After 2 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (6.0 mg, 0.011 mmol, 11%) as a white solid.

[1151] .sup.1H NMR (CD.sub.3OD) 8.66 (d, 1H), 7.85 (s, 1H), 7.62 (dd, 1H), 7.21 (d, 1H), 7.04 (d, 1H), 6.90 (s, 1H), 4.84 (d, 4H), 4.41-4.26 (m, 1H), 3.52 (s, 2H), 3.05 (s, 3H), 2.94 (t, 2H), 2.79 (t, 2H), 2.13-1.99 (m, 2H), 1.42 (dd, 6H).

[1152] LCMS: m/z 536 (M+H).sup.+ (ES.sup.+).

Example 64: 3-(N-(2-(5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide

[1153] ##STR00317##

[1154] A solution of N,N,1-trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P11) (118 mg, 0.51 mmol, 2 eq) and triethylamine (0.21 mL, 1.52 mmol, 6 eq) in dichloromethane (5 mL) was cooled in an ice bath. Then a solution of 2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-H-inden-4-yl)acetyl chloride (Intermediate A2) (110 mg, 0.25 mmol, 1 eq) in anhydrous dichloromethane (5 mL) was added dropwise. After complete addition, the ice bath was removed and the reaction mixture was stirred at room temperature. After stirring over the weekend, the reaction mixture concentrated in vacuo. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (23 mg, 46 mol, 18%).

[1155] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.05 (dd, 1H), 7.12 (d, 1H), 6.97 (d, 1H), 6.91 (dd, 1H), 6.85 (s, 1H), 6.78 (dd, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.46 (s, 2H), 3.10 (d, 6H), 2.92 (t, 2H), 2.82 (t, 2H), 2.05 (p, 2H).

[1156] LC-MS: m/z 498 (M+H).sup.+ (ES.sup.+).

Example 65: 3-(N-(2-(5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide

[1157] ##STR00318##

[1158] To a solution of N,N,1-trimethyl-3-sulfamoyl-H-pyrazole-5-carboxamide (Intermediate P11) (41 mg, 0.18 mmol, 2 eq) in anhydrous dichloromethane (2 mL) was added triethylamine (37 L, 0.26 mmol, 3 eq). The solution was cooled in an ice bath. A solution of 2-(5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetyl chloride (Intermediate A3) (26 mg, 88 mol, 1 eq) in anhydrous dichloromethane (2 mL) was added dropwise. After complete addition, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature. After stirring over the weekend, the reaction mixture was concentrated in vacuo. The crude product was subjected to preparative HPLC (see Experimental Methods, Purification Method 2) to afford the title compound (0.7 mg, 1.0 mol, 2%).

[1159] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.64 (d, 1H), 7.87 (s, 1H), 7.66 (dd, 1H), 7.17 (d, 1H), 7.01 (d, 1H), 6.84 (s, 1H), 3.94 (s, 3H), 3.42 (s, 2H), 3.10 (m, 4H), 2.15 (s, 6H), 1.88 (m, 2H).

[1160] LCMS: m/z 493 (M+H).sup.+ (ES.sup.+).

Example 66: N-((1-Cyclopropyl-1H-pyrazol-3-yl)sulfonyl)-2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetamide

[1161] ##STR00319##

[1162] A solution of 1-cyclopropyl-1H-pyrazole-3-sulfonamide (Intermediate P5) (0.10 g, 0.55 mmol, 2 eq) and triethylamine (0.23 mL, 1.65 mmol, 6 eq) in dichloromethane (5 mL) was cooled in an ice bath. Then a solution of 2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetyl chloride (Intermediate A2) (119 mg, 0.28 mmol, 1 eq) in anhydrous dichloromethane (5 mL) was added dropwise. After complete addition, the ice bath was removed and the reaction mixture was stirred at room temperature.

[1163] After stirring over the weekend, the reaction mixture concentrated in vacuo. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (29 mg, 64 mol, 23%).

[1164] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.06 (d, 1H), 7.69 (d, 1H), 7.13 (d, 1H), 6.98 (d, 1H), 6.89 (d, 1H), 6.76 (s, 1H), 6.65 (d, 1H), 3.91 (s, 3H), 3.77-3.64 (m, 1H), 3.48 (s, 2H), 2.93 (t, 2H), 2.79 (t, 2H), 2.08 (q, 2H), 1.13 (dd, 2H), 1.05 (t, 2H).

[1165] LC-MS: m/z 453 (M+H).sup.+ (ES.sup.+).

Example 67: N-((1-Cyclopropyl-1H-pyrazol-4-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide, potassium salt

[1166] ##STR00320##

[1167] 1-Cyclopropyl-1H-pyrazole-4-sulfonamide (Intermediate P7) (67 mg, 0.36 mmol) and KOtBu (40 mg, 0.36 mmol) were stirred in THF (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride (Intermediate A4) (58 mg, 0.18 mmol) in THF (3 mL) was added dropwise. The mixture was stirred overnight at room temperature and then concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (8 mg, 9%) as a white solid.

[1168] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.04 (s, 1H), 8.02 (d, 1H), 7.74 (d, 1H), 7.02 (dd, 1H), 6.87 (dd, 1H), 6.80-6.65 (m, 2H), 3.89 (s, 3H), 3.66 (m, 1H), 3.39 (s, 2H), 3.11-2.93 (m, 1H), 1.10 (m, 6H), 1.07-0.97 (m, 4H).

[1169] LCMS: m/z 473 (M+H).sup.+ (ES.sup.+); 471 (MH).sup. (ES.sup.).

Example 68: N-((2-Cyclopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide

[1170] ##STR00321##

[1171] To a mixture of 2-cyclopropyl-2H-1,2,3-triazole-4-sulfonamide (Intermediate P6) (70 mg, 371.93 mol, 1 eq) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (113 mg, 371.93 mol, 1 eq) in DMF (2 mL) were added EDC (107 mg, 557.90 mol, 1.5 eq) and DMAP (68 mg, 557.90 mol, 1.5 eq). Then the reaction mixture was stirred at 25 C. for 1 hour. The reaction mixture was purified by reversed phase flash chromatography (0.1% TFA-MeCN) and then further purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase [A: water (0.05% ammonium hydroxide v/v), B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (34.88 mg, 19% yield, 98% purity on LCMS, ammonium salt) as a white solid.

[1172] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.12 (d, 1H), 7.82 (s, 1H), 7.25-6.95 (m, 4H), 6.91 (d, 1H), 6.84-6.81 (m, 2H), 4.16-4.11 (m, 1H), 3.87 (s, 3H), 3.27 (s, 2H), 3.02-2.89 (m, 1H), 1.20-1.10 (m, 4H) and 1.04 (d, 6H).

[1173] LCMS: m/z 474.2 (M+H).sup.+ (ES.sup.+).

Example 69: N-((1-Cyclopropyl-1H-1,2,4-triazol-3-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide

[1174] ##STR00322##

[1175] To a mixture of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (113 mg, 371.93 mol, 1 eq) in DMF (2 mL) were added 1-cyclopropyl-1H-1,2,4-triazole-3-sulfonamide (Intermediate P12) (70 mg, 371.93 mol, 1 eq), EDC (107 mg, 557.90 mol, 1.5 eq) and DMAP (68 mg, 557.90 mol, 1.5 eq). The reaction mixture was stirred at 25 C. for 1 hour, and then filtered. The filtrate was purified by reversed phase flash chromatography (water (0.1% TFA)-MeCN), and then further purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase [A: water (0.05% ammonium hydroxide v/v), B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (71.2 mg, 100% yield, 100% purity on LCMS, ammonium salt) as white solid.

[1176] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.60 (s, 1H), 8.17 (d, 1H), 7.14-7.10 (m, 4H), 7.00 (s, 1H), 6.84-6.79 (m, 2H), 3.88 (s, 3H), 3.80-3.76 (m, 1H), 3.32 (s, 2H), 3.10-3.01 (m, 1H), 1.11 (d, 6H) and 1.09-1.05 (m, 4H).

[1177] LCMS: m/z 474.2 (M+H).sup.+ (ES.sup.+).

Example 70: N-((1-Cyclopropyl-1H-1,2,4-triazol-3-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetamide

[1178] ##STR00323##

[1179] To the solution of 2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetic acid (Intermediate A5, Step J) (102 mg, 371.93 mol, 1 eq), EDC (143 mg, 743.86 mol, 2 eq) and DMAP (68 mg, 557.90 mol, 1.5 eq) in DMF (1 mL) was added 1-cyclopropyl-1H-1,2,4-triazole-3-sulfonamide (Intermediate P12) (70 mg, 371.93 mol, 1 eq). The resulting mixture was stirred at 20 C. for 1 hour. The reaction mixture was purified directly by reversed phase flash chromatography (0.1% TFA in water-MeCN), and then further purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase [A: water (0.05% ammonium hydroxide v/v), B: MeCN]; B %: 8%-35%, 10 min) to give the title compound (22.10 mg, 13% yield, 100% purity on LCMS, ammonium salt) as a white solid.

[1180] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.65 (s, 1H), 8.58 (d, 1H), 8.50 (s, 1H), 7.80-7.76 (m, 1H), 7.44 (dd, 1H), 7.28-6.90 (m, 4H), 6.87 (dd, 1H), 3.81-3.80 (m, 1H), 3.30 (s, 2H), 3.06-3.04 (m, 1H), 1.12 (d, 6H) and 1.08-1.03 (m, 4H).

[1181] LCMS: m/z 444.3 (M+H).sup.+ (ES.sup.+).

Example 71: N-((1-Cyclopropyl-1H-pyrazol-4-yl)sulfonyl)-2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetamide

[1182] ##STR00324##

[1183] To a mixture of 1-cyclopropyl-1H-pyrazole-4-sulfonamide (Intermediate P7) (50 mg, 267.07 mol, 1 eq) and 2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid (Intermediate A2, Step F, non salt form) (76 mg, 267.07 mol, 1 eq) in DMF (3 mL) were added EDC (102 mg, 534.13 mol, 2 eq) and DMAP (65 mg, 534.13 mol, 2 eq) in one portion under nitrogen. Then the reaction mixture was stirred at 25 C. for 1 hour. The reaction mixture was purified by reversed phase flash chromatography (0.05% NH.sub.3.H.sub.2O-MeCN), and then further purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase [A: water (10 mM NH.sub.4HCO), B: MeCN]; B %: 15%-45%, 10 min) to give the title compound (29.78 mg, 49% yield, 99.4% purity on LCMS) as a white solid.

[1184] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.33 (s, 1H), 8.06 (d, 1H), 7.72 (s, 1H), 7.17 (d, 1H), 6.98 (d, 1H), 6.70 (d, 1H), 6.60 (s, 1H), 3.86 (s, 3H), 3.84-3.82 (m, 1H), 3.34 (s, 2H), 2.86 (t, 2H), 2.52 (t, 2H), 1.98-1.94 (m, 2H), 1.07-1.06 (m, 2H) and 1.01-0.98 (m, 2H).

[1185] LCMS: m/z 453.3 (M+H).sup.+ (ES.sup.+).

Example 72: N-((2-Cyclopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetamide

[1186] ##STR00325##

[1187] To a solution of 2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetic acid (Intermediate A5, Step J) (102 mg, 371.93 mol, 1 eq) in DMF (1 mL) were added EDC (143 mg, 743.86 mol, 2 eq), DMAP (68 mg, 557.90 mol, 1.5 eq) and 2-cyclopropyl-2H-1,2,3-triazole-4-sulfonamide (Intermediate P6) (70 mg, 371.93 mol, 1 eq). The reaction mixture was stirred at 20 C. for 1 hour, and then filtered. The filtrate was purified by reversed phase flash chromatography (0.1% TFA in water-MeCN), and then further purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 m; mobile phase [A: water (10 mM NH.sub.4HCO.sub.3), B: MeCN]; B %: 23%-46%, 7 min) to give the title compound (21.66 mg, 13% yield, 100% purity on LCMS) as a white solid.

[1188] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.50 (d, 1H), 8.45 (d, 1H), 7.83 (s, 1H), 7.56 (d, 1H), 7.30-7.27 (m, 1H), 7.03 (dd, 1H), 6.71 (dd, 1H), 4.04-3.99 (m, 1H), 3.48 (s, 2H), 3.02-2.98 (m, 1H), 1.31-1.28 (m, 2H), 1.12 (d, 6H) and 1.07-1.05 (m, 2H).

[1189] LCMS: m/z 444.1 (M+H).sup.+ (ES.sup.+).

Example 73: N-((5-((Dimethylamino)methyl)-1-methyl-H-pyrazol-3-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetamide

[1190] ##STR00326##

[1191] To a suspension of 5-((dimethylamino)methyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P10) (49 mg, 0.22 mmol, 1.5 eq) in anhydrous tetrahydrofuran (2 mL) was added potassium tert-butoxide (1M solution in tetrahydrofuran, 0.23 mL, 0.22 mmol, 1.5 eq). The suspension was stirred for 30 minutes at room temperature and then cooled in an ice bath. To the suspension was added a solution of 2-(4-fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetyl chloride (Intermediate A6) (44 mg, 0.15 mmol, 1 eq) in anhydrous tetrahydrofuran (2 mL). After complete addition, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After stirring overnight, the reaction mixture was concentrated in vacuo. The crude product was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (2.0 mg, 4.2 mol, 3%).

[1192] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.52-8.47 (m, 2H), 7.44-7.35 (m, 2H), 7.05 (dd, 1H), 6.76 (dd, 1H), 6.54 (s, 1H), 3.89 (d, 2H), 3.50 (s, 3H), 3.42 (s, 2H), 3.15-3.03 (m, 1H), 2.25 (s, 6H), 1.13 (d, 6H).

[1193] LC-MS: m/z 474 (M+H).sup.+ (ES.sup.+).

Example 74: 2-(5-(2-Cyanopyridin-4-yl)-2,3-dihydro-H-inden-4-yl)-N-((1-cyclopropyl-1H-pyrazol-4-yl)sulfonyl)acetamide

[1194] ##STR00327##

[1195] To a suspension of 1-cyclopropyl-1H-pyrazole-4-sulfonamide (Intermediate P7) (28 mg, 0.15 mmol, 1.5 eq) in anhydrous tetrahydrofuran (2 mL) was added potassium tert-butoxide (16 mg, 0.14 mmol, 1.4 eq). The suspension was stirred for 30 minutes at room temperature and then cooled in an ice bath. To the suspension was added a solution of 2-(5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetyl chloride (Intermediate A3) (30 mg, 0.10 mmol, 1 eq) in anhydrous tetrahydrofuran (2 mL). After complete addition, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After stirring overnight, the reaction mixture was concentrated in vacuo. The crude was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1). To increase the final purity, the product was subsequently purified by prep HPLC (see Experimental Methods, Purification Method 2) to afford the title compound (1.0 mg, 2 mol, 2%).

[1196] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.59 (d, 1H), 8.26 (s, 1H), 7.81 (s, 1H), 7.74 (s, 1H), 7.45 (dd, 1H), 7.25 (d, 1H), 7.05 (d, 1H), 3.78 (s, 1H), 3.51 (s, 2H), 2.97 (t, 2H), 2.73 (t, 2H), 2.08 (t, 2H), 1.30 (d, 2H), 1.18-0.92 (m, 2H).

[1197] LC-MS: m/z 448 (M+H).sup.+ (ES.sup.+).

Example 75: N-(((((1S)-7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methyl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide, potassium salt

[1198] ##STR00328##

[1199] ((1S)-7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonamide (50 mg, 0.22 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (130 mg, 0.22 mmol) were stirred in DCM (6 mL). EDC (150 mg, 0.76 mmol) and DMAP (92 mg, 0.76 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KO.sup.tBu (97 mg, 0.86 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (39 mg, 35%) as a white solid.

[1200] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.12 (dd, 1H), 7.07 (dd, 1H), 6.98 (dd, 1H), 6.84 (dd, 1H), 6.76 (dd, 1H), 3.92 (s, 3H), 3.60 (d, 1H), 3.48 (s, 2H), 3.26-3.09 (m, 2H), 2.60-2.44 (m, 1H), 2.35 (dt, 1H), 2.05 (m, 2H), 1.90 (d, 1H), 1.65 (td, 1H), 1.49-1.35 (m, 1H), 1.24 (dd, 6H), 1.06 (s, 3H), 0.85 (s, 3H).

[1201] LCMS: m/z 517 (M+H).sup.+ (ES.sup.+); 515 (MH).sup. (ES.sup.).

Example 76: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N(N-methyl-N-(1-methylpyrrolidin-3-yl)sulfamoyl)acetamide, potassium salt

[1202] ##STR00329##

[1203] N-Methyl-N-(1-methylpyrrolidin-3-yl)sulfamide (Intermediate P8) (40 mg, 0.21 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (120 mg, 0.21 mmol) were stirred in DCM (6 mL). EDC (140 mg, 0.72 mmol) and DMAP (88 mg, 0.72 mmol) were added. The mixture was stirred overnight and concentrated. The residue was dissolved in DMSO (0.6 mL) and KOtBu (93 mg, 0.83 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford a hygroscopic oil (30 mg). The oil was taken up in DCM and washed with 5% NH.sub.4Cl (aqueous, 2 mL). The organic phase was concentrated and the residue was dissolved in DMSO (0.6 mL) and KO.sup.tBu (93 mg, 0.83 mmol) was added. The mixture was subjected once more to reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (12 mg, 12%) as a white solid.

[1204] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.13 (d, 1H), 7.12-7.00 (m, 2H), 6.90 (d, 1H), 6.76 (dd, 1H), 3.93 (s, 3H), 3.42 (s, 2H), 3.19 (dd, 1H), 2.70 (s, 3H), 2.64-2.34 (m, 5H), 2.28 (s, 3H), 1.96 (m, 1H), 1.79 (dd, 1H), 1.25 (dd, 6H).

[1205] LCMS: m/z 479 (M+H).sup.+ (ES.sup.+); 477 (MH).sup. (ES.sup.).

Example 77: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((((1R,2R,4S)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptan-1-yl)methyl)sulfonyl)acetamide, potassium salt

[1206] ##STR00330##

[1207] ((1R,2R,4S)-2-Hydroxy-7,7-dimethylbicyclo[2.2.]heptan-1-yl)methanesulfonamide (Intermediate P17) (39 mg, 0.17 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (98 mg, 0.17 mmol) were stirred in DCM (6 mL). EDC (110 mg, 0.59 mmol) and DMAP (71 mg, 0.59 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KO.sup.tBu (75 mg, 0.67 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (33 mg, 38%) as a white solid.

[1208] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.12 (dd, 1H), 7.07 (dd, 1H), 6.98 (dd, 1H), 6.86 (dd, 1H), 6.75 (dd, 1H), 4.10 (dd, 1H), 3.92 (s, 3H), 3.54 (d, 1H), 3.50-3.44 (s, 2H), 3.23 (m, 1H), 3.20 (d, 1H), 1.79-1.61 (m, 4H), 1.47 (m, 2H), 1.24 (dd, 6H), 1.10 (m, 1H), 1.05 (s, 3H), 0.84 (s, 3H).

[1209] LCMS: m/z 519 (M+H).sup.+ (ES.sup.+); 517 (MH).sup. (ES.sup.).

Example 78: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((4-hydroxy-4-methylpentyl)sulfonyl)acetamide, potassium salt

[1210] ##STR00331##

[1211] 4-Hydroxy-4-methylpentane-1-sulfonamide (Intermediate P18) (36 mg, 0.20 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (120 mg, 0.2 mmol) were stirred in DCM (6 mL). EDC (130 mg, 0.7 mmol) and DMAP (85 mg, 0.7 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KOtBu (67 mg, 0.6 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (56 mg, 60%) as a white solid.

[1212] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.17-8.08 (m, 1H), 7.12-7.04 (m, 1H), 7.04-6.98 (m, 1H), 6.84 (d, 1H), 6.75 (dd, 1H), 3.92 (s, 3H), 3.47 (s, 2H), 3.25-3.11 (m, 3H), 1.83 (tdd, 2H), 1.64-1.49 (m, 2H), 1.24 (d, 6H), 1.18 (s, 6H).

[1213] LCMS: m/z 467 (M+H).sup.+ (ES.sup.+); 465 (MH).sup. (ES.sup.).

Example 79: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((4-fluoro-3-(2-hydroxypropan-2-yl)phenyl)sulfonyl)acetamide, potassium salt

[1214] ##STR00332##

[1215] 4-Fluoro-3-(2-hydroxypropan-2-yl)benzenesulfonamide (Intermediate P19) (52 mg, 0.22 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (130 mg, 0.22 mmol) were stirred in DCM (6 mL). EDC (150 mg, 0.78 mmol) and DMAP (95 mg, 0.78 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL. The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KO.sup.tBu (100 mg, 0.89 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (49 mg, 42%) as a white solid.

[1216] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.26 (dd, 1H), 8.00 (dd, 1H), 7.80 (ddd, 1H), 7.11 (dd, 1H), 6.99 (dd, 1H), 6.83 (dd, 1H), 6.76-6.66 (m, 2H), 3.88 (s, 3H), 3.41 (s, 2H), 2.96 (p, 1H), 1.57 (d, 6H), 1.05 (d, 6H).

[1217] LCMS: m/z 519 (M+H).sup.+ (ES.sup.+); 517 (MH).sup. (ES.sup.).

Example 80: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((4-(2-hydroxypropan-2-yl)phenyl)sulfonyl)acetamide, potassium salt

[1218] ##STR00333##

[1219] 4-(2-Hydroxypropan-2-yl)benzenesulfonamide (Intermediate P20) (60 mg, 0.28 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (160 mg, 0.28 mmol) were stirred in DCM (6 mL). EDC (190 mg, 0.98 mmol) and DMAP (120 mg, 0.98 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KO.sup.tBu (94 mg, 0.84 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (13 mg, 9%) as a white solid.

[1220] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.00 (d, 1H), 7.86 (d, 2H), 7.56 (d, 2H), 6.98 (dd, 1H), 6.88-6.80 (m, 1H), 6.77 (s, 1H), 6.70 (dd, 1H), 3.90 (s, 3H), 3.42 (s, 2H), 2.99 (m, 1H), 1.52 (s, 6H), 1.06 (d, 6H).

[1221] LCMS: m/z 501 (M+H).sup.+ (ES.sup.+); 499 (MH).sup. (ES.sup.).

Example 81: N-((3-(2-Cyanopropan-2-yl)phenyl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide, potassium salt

[1222] ##STR00334##

[1223] 3-(2-Cyanopropan-2-yl)benzenesulfonamide (Intermediate P21) (15 mg, 0.067 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (39 mg, 0.067 mmol) were stirred in DCM (6 mL). EDC (45 mg, 0.23 mmol) and DMAP (29 mg, 0.23 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KOtBu (30 mg, 0.27 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (21 mg, 62%) as a white solid.

[1224] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.08 (t, 1H), 7.99 (dd, 1H), 7.87 (dt, 1H), 7.68 (ddd, 1H), 7.51 (t, 1H), 6.99 (dd, 1H), 6.85 (dd, 1H), 6.76 (dd, 1H), 6.70 (dd, 1H), 3.88 (s, 3H), 3.42 (s, 2H), 2.99 (dd, 1H), 1.74 (s, 6H), 1.06 (d, 6H).

[1225] LCMS: m/z 510 (M+H).sup.+ (ES.sup.+); 508 (MH).sup. (ES.sup.).

Example 82: 2-(4-Fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)-N-((4-(2-hydroxypropan-2-yl)-2-methylphenyl)sulfonyl)acetamide, potassium salt

[1226] ##STR00335##

[1227] 4-(2-Hydroxypropan-2-yl)-2-methylbenzenesulfonamide (Intermediate P3) (18 mg, 0.079 mmol) and 2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetic acid (Intermediate A5, Step J) (21 mg, 0.079 mmol) were stirred in DCM (6 mL). EDC (53 mg, 0.27 mmol) and DMAP (34 mg, 0.27 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 0.5M citric acid (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KOtBu (35 mg, 0.31 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (11 mg, 29%) as a white solid.

[1228] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.50 (dd, 1H), 8.43 (dd, 1H), 7.91 (d, 1H), 7.75 (dt, 1H), 7.41-7.27 (m, 3H), 6.99 (dd, 1H), 6.71 (dd, 1H), 3.43 (s, 2H), 3.12-2.94 (m, 1H), 2.61 (s, 3H), 1.50 (s, 6H), 1.08 (d, 6H).

[1229] LCMS: m/z 485 (M+H).sup.+ (ES.sup.+); 483 (MH).sup. (ES.sup.).

Example 83: N-((4-(2-Aminopropan-2-yl)-3-fluorophenyl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide, TFA salt

[1230] ##STR00336##

[1231] tert-Butyl (2-(2-fluoro-4-(N-(2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl)sulfamoyl)phenyl)propan-2-yl)carbamate (Example 90) (110 mg, 0.15 mmol) was dissolved in DCM (1 mL) and TFA (0.7 mL). The reaction mixture was stirred overnight at room temperature, and then concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (20 mg, 26%) as a white solid.

[1232] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.08-7.99 (m, 1H), 7.74 (dd, 1H), 7.67 (dd, 1H), 7.52 (t, 1H), 7.00 (dd, 1H), 6.85 (dd, 1H), 6.78-6.74 (m, 1H), 6.71 (dd, 1H), 3.92 (s, 3H), 3.43 (s, 2H), 3.03 (m, 1H), 1.71 (s, 6H), 1.10 (d, 6H).

[1233] LCMS: m/z 518 (M+H).sup.+ (ES.sup.+); 516 (MH).sup. (ES.sup.).

Example 84: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((3-fluoro-4-(2-hydroxypropan-2-yl)phenyl)sulfonyl)acetamide, potassium salt

[1234] ##STR00337##

[1235] 3-Fluoro-4-(2-hydroxypropan-2-yl)benzenesulfonamide (Intermediate P22) (85 mg, 0.29 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (170 mg, 0.29 mmol) were stirred in DCM (6 mL). EDC (200 mg, 1 mmol) and DMAP (120 mg, 1 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KO.sup.tBu (98 mg, 0.87 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) followed by a second purification with the same method to afford the title compound (22 mg, 15%) as a white solid.

[1236] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.02 (dd, 1H), 7.77-7.63 (m, 2H), 7.60-7.51 (m, 1H), 6.99 (dd, 1H), 6.84 (dd, 1H), 6.77 (dd, 1H), 6.70 (dd, 1H), 3.91 (s, 3H), 3.42 (s, 2H), 3.08-2.91 (m, 1H), 1.57 (d, 6H), 1.07 (d, 6H).

[1237] LCMS: m/z 519 (M+H).sup.+ (ES.sup.+); 517 (MH).sup. (ES.sup.).

Example 85: N-((4-(2-Hydroxypropan-2-yl)-2-methylphenyl)sulfonyl)-2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetamide, potassium salt

[1238] ##STR00338##

[1239] 4-(2-Hydroxypropan-2-yl)-2-methylbenzenesulfonamide (Intermediate P3) (49 mg, 0.17 mmol) and 2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid (Intermediate A2, Step F, non salt form) (48 mg, 0.17 mmol) were stirred in DCM (6 mL). EDC (66 mg, 0.34 mmol) and DMAP (42 mg, 0.34 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KO.sup.tBu (58 mg, 0.51 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (23 mg, 27%) as a light yellow solid.

[1240] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.01 (d, 1H), 7.91 (d, 1H), 7.42-7.27 (m, 2H), 7.08 (d, 1H), 6.94 (d, 1H), 6.86 (dd, 1H), 6.78 (d, 1H), 3.90 (s, 3H), 3.44 (s, 2H), 2.89 (t, 2H), 2.73 (t, 2H), 2.60 (s, 3H), 2.03 (m, 2H), 1.51 (s, 6H).

[1241] LCMS: m/z 495 (M+H).sup.+ (ES.sup.+); 493 (MH).sup. (ES.sup.).

Example 86: 2-(4-Fluoro-2-(2-fluoropropan-2-yl)-6-(2-methoxypyridin-4-yl)phenyl)-N-((4-(2-hydroxypropan-2-yl)-2-methylphenyl)sulfonyl)acetamide

[1242] ##STR00339##

[1243] 4-(2-Hydroxypropan-2-yl)-2-methylbenzenesulfonamide (Intermediate P3) (17 mg, 0.059 mmol) and 2-(4-fluoro-2-(2-fluoropropan-2-yl)-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A10) (19 mg, 0.059 mmol) were stirred in DCM (6 mL). EDC (23 mg, 0.12 mmol) and DMAP (14 mg, 0.12 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (13 mg, 41%) as a white solid.

[1244] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 7.96 (d, 1H), 7.86 (d, 1H), 7.36 (s, 1H), 7.30 (d, 1H), 7.13 (dd, 1H), 6.81-6.71 (m, 2H), 6.67 (s, 1H), 3.92 (s, 3H), 3.63 (s, 2H), 2.52 (s, 3H), 1.66 (s, 3H), 1.59 (s, 3H), 1.52 (s, 6H).

[1245] LCMS: m/z 533 (M+H).sup.+ (ES.sup.+); 531 (MH).sup. (ES.sup.).

Example 87: 2-(4-Fluoro-2-(2-fluoropropan-2-yl)-6-(2-methoxypyridin-4-yl)phenyl)-N-((4-(2-hydroxypropan-2-yl)thiophen-2-yl)sulfonyl)acetamide

[1246] ##STR00340##

[1247] 4-(2-Hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate P14) (13 mg, 0.059 mmol) and 2-(4-fluoro-2-(2-fluoropropan-2-yl)-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A10) (19 mg, 0.059 mmol) were stirred in DCM (6 mL). EDC (23 mg, 0.12 mmol) and DMAP (14 mg, 0.12 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (6 mg, 19%) as a light brown solid.

[1248] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 7.95-7.88 (m, 1H), 7.59 (d, 1H), 7.38 (d, 1H), 7.18 (dd, 1H), 6.88-6.78 (m, 2H), 6.74-6.67 (m, 1H), 3.89 (s, 3H), 3.60 (s, 2H), 1.70 (s, 3H), 1.63 (s, 3H), 1.51 (s, 6H).

[1249] LCMS: m/z 525 (M+H).sup.+ (ES.sup.+); 523 (MH).sup. (ES.sup.).

Example 88: N-((4-(2-Acetamidopropan-2-yl)-3-fluorophenyl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide

[1250] ##STR00341##

[1251] N-((4-(2-Aminopropan-2-yl)-3-fluorophenyl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide (Example 83) (24 mg, 0.046 mmol) and triethylamine (19 L, 0.14 mmol) were stirred in DCM (1 mL). Acetyl chloride (3.6 mg, 0.046 mmol) was added and the reaction mixture was stirred overnight. Further acetyl chloride (5 mg) was added. The reaction mixture was stirred overnight, and then diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (5 mg, 19%) as a white solid.

[1252] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.03 (d, 1H), 7.63 (dd, 1H), 7.56 (dd, 1H), 7.43 (t, 1H), 6.99 (dd, 1H), 6.84 (dd, 1H), 6.77 (s, 1H), 6.70 (dd, 1H), 3.91 (s, 3H), 3.42 (s, 2H), 3.08-2.93 (m, 1H), 1.90 (s, 3H), 1.69 (s, 6H), 1.08 (d, 6H).

[1253] LCMS: m/z 560 (M+H).sup.+ (ES.sup.+); 58 (MH).sup. (ES.sup.).

Example 89: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((3-(2-hydroxypropan-2-yl)phenyl)sulfonyl)acetamide, potassium salt

[1254] ##STR00342##

[1255] 3-(2-Hydroxypropan-2-yl)benzenesulfonamide (Intermediate P23) (32 mg, 0.15 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (45 mg, 0.15 mmol) were stirred in DCM (6 mL). EDC (57 mg, 0.3 mmol) and DMAP (36 mg, 0.3 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KO.sup.tBu (50 mg, 0.45 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (37 mg, 50%) as a white solid.

[1256] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.08 (t, 1H), 7.97 (dd, 1H), 7.76 (ddd, 1H), 7.62 (ddd, 1H), 7.40 (t, 1H), 6.99 (dd, 1H), 6.84 (dd, 1H), 6.76 (dd, 1H), 6.70 (dd, 1H), 3.87 (s, 3H), 3.42 (s, 2H), 2.99 (m, 1H), 1.53 (s, 6H), 1.06 (d, 6H).

[1257] LCMS: m/z 501 (M+H).sup.+ (ES.sup.+); 499 (MH).sup. (ES.sup.).

Example 90: tert-Butyl (2-(2-fluoro-4-(N-(2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl)sulfamoyl)phenyl)propan-2-yl)carbamate

[1258] ##STR00343##

[1259] tert-Butyl(2-(2-fluoro-4-sulfamoylphenyl)propan-2-yl)carbamate (Intermediate P24) (90 mg, 0.22 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (130 mg, 0.22 mmol) were stirred in DCM (6 mL). EDC (150 mg, 0.76 mmol) and DMAP (93 mg, 0.76 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M citric acid (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and the mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (82 mg, 61%) as a white solid.

[1260] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.03 (d, 1H), 7.64 (dd, 1H), 7.57 (dd, 1H), 7.44 (t, 1H), 6.99 (dd, 1H), 6.85 (dd, 1H), 6.77 (s, 1H), 6.70 (dd, 1H), 3.91 (s, 3H), 3.42 (s, 2H), 3.02 (m, 1H), 1.64 (d, 6H), 1.50-1.25 (m, 9H), 1.09 (d, 6H).

[1261] LCMS: m/z 618 (M+H).sup.+ (ES.sup.+); 616 (MH).sup. (ES.sup.).

Example 91: N-((4-(2-(Dimethylamino)propan-2-yl)-3-fluorophenyl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide, potassium salt

[1262] ##STR00344##

[1263] 4-(2-(Dimethylamino)propan-2-yl)-3-fluorobenzenesulfonamide (Intermediate P25) (22 mg, 0.085 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (26 mg, 0.085 mmol) were stirred in DCM (6 mL). EDC (32 mg, 0.17 mmol) and DMAP (21 mg, 0.17 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KO.sup.tBu (38 mg, 0.34 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (18 mg, 39%) as a white solid.

[1264] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.05 (d, 1H), 7.81-7.62 (m, 3H), 7.01 (dd, 1H), 6.85 (dd, 1H), 6.71 (m, 2H), 3.93 (s, 3H), 3.44 (s, 2H), 3.04 (m, 1H), 2.62 (s, 6H), 1.77 (s, 6H), 1.10 (d, 6H).

[1265] LCMS: m/z 546 (M+H).sup.+ (ES.sup.+); 544 (MH).sup. (ES.sup.).

Example 92: Methyl 2-fluoro-5-(N-(2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl)sulfamoyl)benzoate

[1266] ##STR00345##

[1267] Methyl 2-fluoro-5-sulfamoylbenzoate (100 mg, 0.43 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (131 mg, 0.43 mmol) were stirred in DCM (6 mL). EDC (166 mg, 0.87 mmol) and DMAP (106 mg, 0.87 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (3 mg, 1%) as a white solid.

[1268] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.49 (dd, 1H), 8.14 (ddd, 1H), 8.01 (d, 1H), 7.33 (dd, 1H), 7.01 (dd, 1H), 6.78 (dd, 1H), 6.75-6.70 (m, 1H), 6.65 (s, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.43 (s, 2H), 2.91 (td, 1H), 1.08 (d, 6H).

[1269] LCMS: m/z 519 (M+H).sup.+ (ES.sup.+); 517 (MH).sup. (ES.sup.).

Example 93: N-((4-Chlorophenyl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide, potassium salt

[1270] ##STR00346##

[1271] 4-Chlorobenzenesulfonamide (50 mg, 0.26 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (79 mg, 0.26 mmol) were stirred in DCM (6 mL). EDC (100 mg, 0.52 mmol) and DMAP (64 mg, 0.52 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KO.sup.tBu (88 mg, 0.78 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (59 mg, 47%) as a white solid.

[1272] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.01 (dd, 1H), 7.93-7.82 (m, 2H), 7.52-7.39 (m, 2H), 7.00 (dd, 1H), 6.83 (dd, 1H), 6.75-6.66 (m, 2H), 3.89 (s, 3H), 3.42 (s, 2H), 3.06-2.90 (m, 1H), 1.09 (d, 6H).

[1273] LCMS: m/z 477 (M+H).sup.+ (ES.sup.+); 475 (MH).sup. (ES.sup.).

Example 94: N-((1,3-Dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide

[1274] ##STR00347##

[1275] 1,3-Dimethyl-1H-pyrazolo[3,4-b]pyridine-5-sulfonamide (45 mg, 0.2 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (60 mg, 0.2 mmol) were stirred in DCM (6 mL). EDC (76 mg, 0.4 mmol) and DMAP (49 mg, 0.4 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (16 mg, 16%) as a white solid.

[1276] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 9.00 (d, 1H), 8.69 (d, 1H), 7.93 (d, 1H), 6.96 (dd, 1H), 6.76 (dd, 1H), 6.74-6.63 (m, 2H), 4.06 (s, 3H), 3.81 (s, 3H), 3.41 (s, 2H), 3.01-2.88 (m, 1H), 2.60 (s, 3H), 0.99 (d, 6H).

[1277] LCMS: m/z 512 (M+H).sup.+ (ES.sup.+); 510 (MH).sup. (ES.sup.).

Example 95: N-((4-Acetamidophenyl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide

[1278] ##STR00348##

[1279] N-(4-Sulfamoylphenyl)acetamide (47 mg, 0.22 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (67 mg, 0.22 mmol) were stirred in DCM (6 mL). EDC (84 mg, 0.44 mmol) and DMAP (54 mg, 0.44 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (42 mg, 38%) as a white solid.

[1280] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 7.98 (dd, 1H), 7.95-7.85 (m, 2H), 7.81-7.71 (m, 2H), 7.04 (dd, 1H), 6.73 (dd, 1H), 6.65 (dd, 1H), 6.59 (d, 1H), 3.88 (s, 3H), 3.46 (s, 2H), 2.82 (dd, 1H), 2.16 (s, 3H), 1.09 (d, 6H).

[1281] LCMS: m/z 500 (M+H).sup.+ (ES.sup.+); 498 (MH).sup. (ES.sup.).

Example 96: 2-Chloro-4-(N-(2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl)sulfamoyl)-N,N-dimethylbenzamide, potassium salt

Step A: 2-Chloro-4-(N-(2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl)sulfamoyl)benzoic acid, potassium salt

[1282] ##STR00349##

[1283] Methyl 2-chloro-4-sulfamoylbenzoate (150 mg, 0.6 mmol) and 2-(4-fluoro-2-isopropyl-6-(6-methoxypyridin-3-yl)phenyl)acetic acid (Intermediate A11, non salt form) (182 mg, 0.6 mmol) were stirred in DCM (6 mL). EDC (230 mg, 1.2 mmol) and DMAP (147 mg, 1.2 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KOBu (169 mg, 1.5 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (177 mg, 59%) as a white solid.

[1284] LCMS: m/z 521 (M+H).sup.+ (ES.sup.+); 519 (MH).sup. (ES.sup.).

Step B: 2-Chloro-4-(N-(2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl)sulfamoyl)-N,N-dimethylbenzamide, potassium salt

[1285] ##STR00350##

[1286] 2-Chloro-4-(N-(2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl)sulfamoyl)benzoic acid, potassium salt (67 mg, 0.12 mmol) and dimethylamine (0.1 mL, 0.24 mmol) were stirred in DCM (6 mL). EDC (46 mg, 0.24 mmol) and DMAP (29 mg, 0.24 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KOBu (27 mg, 0.24 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (22 mg, 33%) as a white solid.

[1287] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.07 (dd, 1H), 7.99 (d, 1H), 7.90 (dd, 1H), 7.42 (d, 1H), 7.00 (dd, 1H), 6.85 (dd, 1H), 6.79-6.66 (m, 2H), 3.91 (d, 3H), 3.43 (s, 2H), 3.12 (s, 3H), 3.03 (dd, 1H), 2.86 (s, 3H), 1.11 (d, 6H).

[1288] LCMS: m/z 548 (M+H).sup.+ (ES.sup.+); 546 (MH).sup. (ES.sup.).

Example 97: 2-(4-Fluoro-2-isopropyl-6-(6-methoxypyridin-3-yl)phenyl)-N-((4-(2-hydroxypropan-2-yl)-2-methylphenyl)sulfonyl)acetamide, potassium salt

[1289] ##STR00351##

[1290] 4-(2-Hydroxypropan-2-yl)-2-methylbenzenesulfonamide (Intermediate P3) (13 mg, 0.056 mmol) and 2-(4-fluoro-2-isopropyl-6-(6-methoxypyridin-3-yl)phenyl)acetic acid, TFA salt (Intermediate A11) (30 mg, 0.056 mmol) were stirred in DCM (6 mL). EDC (38 mg, 0.2 mmol) and DMAP (24 mg, 0.2 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KOtBu (19 mg, 0.17 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (11 mg, 38%) as a white solid.

[1291] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 7.98 (d, 1H), 7.92 (d, 1H), 7.55 (dd, 1H), 7.38 (s, 1H), 7.32 (d, 1H), 6.93 (dd, 1H), 6.76-6.70 (m, 1H), 6.67 (dd, 1H), 3.95 (s, 3H), 3.46 (s, 2H), 3.05-2.92 (m, 1H), 2.62 (s, 3H), 1.50 (s, 6H), 1.07 (d, 6H).

[1292] LCMS: m/z 515 (M+H).sup.+ (ES.sup.+); 513 (MH).sup. (ES.sup.).

Example 98: N-((3-Chloro-4-(2-hydroxypropan-2-yl)phenyl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide, potassium salt

[1293] ##STR00352##

[1294] 3-Chloro-4-(2-hydroxypropan-2-yl)benzenesulfonamide (Intermediate P26) (65 mg, 0.26 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (39 mg, 0.13 mmol) were stirred in DCM (6 mL). EDC (50 mg, 0.26 mmol) and DMAP (32 mg, 0.26 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KOtBu (29 mg, 0.26 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (34 mg, 49%) as a white solid.

[1295] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.03 (dd, 1H), 7.94-7.86 (m, 2H), 7.79 (dd, 1H), 6.99 (dd, 1H), 6.85 (dd, 1H), 6.77 (dd, 1H), 6.71 (dd, 1H), 3.90 (s, 3H), 3.42 (s, 2H), 3.04-2.89 (m, 1H), 1.68 (s, 6H), 1.07 (d, 6H).

[1296] LCMS: m/z 535 (M+H).sup.+ (ES.sup.+); 533 (MH).sup. (ES.sup.).

Example 99: 2-(4-Fluoro-2-isopropyl-6-(4-methoxypyridin-3-yl)phenyl)-N-((4-(2-hydroxypropan-2-yl)thiophen-2-yl)sulfonyl)acetamide, potassium salt

[1297] ##STR00353##

[1298] 4-(2-Hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate P14) (18 mg, 0.082 mmol) and 2-(4-fluoro-2-isopropyl-6-(4-methoxypyridin-3-yl)phenyl)acetic acid (Intermediate A12) (25 mg, 0.082 mmol) were stirred in DCM (6 mL). EDC (32 mg, 0.16 mmol) and DMAP (20 mg, 0.16 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KOtBu (18 mg, 0.16 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (17 mg, 41%) as a white solid.

[1299] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.02 (dd, 1H), 7.69-7.55 (m, 2H), 7.41 (d, 1H), 6.99 (dd, 1H), 6.78-6.61 (m, 2H), 3.92 (s, 3H), 3.45 (s, 2H), 3.14-2.96 (m, 1H), 1.51 (s, 6H), 1.12 (d, 6H).

[1300] LCMS: m/z 507 (M+H).sup.+ (ES.sup.+); 505 (MH).sup. (ES.sup.).

Example 100: 2-(4-Fluoro-2-isopropyl-6-(3-methylpyridin-4-yl)phenyl)-N-((4-(2-hydroxypropan-2-yl)thiophen-2-yl)sulfonyl)acetamide, potassium salt

[1301] ##STR00354##

[1302] 4-(2-Hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate P14) (13 mg, 0.059 mmol) and 2-(4-fluoro-2-isopropyl-6-(3-methylpyridin-4-yl)phenyl)acetic acid (Intermediate A13) (17 mg, 0.059 mmol) were stirred in DCM (6 mL). EDC (23 mg, 0.12 mmol) and DMAP (14 mg, 0.12 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KOtBu (13 mg, 0.12 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (5 mg, 17%) as a white solid.

[1303] .sup.1H NMR (300 MHz, Methanol-d.sub.4), rotamer mixture, 8.38 (s, 1H), 8.19 (d, 1H), 7.58 (d, 1H), 7.38 (d, 1H), 7.15 (d, 1H), 7.03 (dd, 1H), 6.60 (dd, 1H), 3.46 (m, 1H), 3.14-3.05 (m, 2H), 2.02 (s, 3H), 1.50 (s, 6H), 1.15 (m, 6H).

[1304] LCMS: m/z 491 (M+H).sup.+ (ES.sup.+); 489 (MH).sup. (ES.sup.).

Example 101: N-((4-Chloro-3-methylphenyl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide, potassium salt

[1305] ##STR00355##

[1306] 4-Chloro-3-methylbenzenesulfonamide (32 mg, 0.16 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (47 mg, 0.16 mmol) were stirred in DCM (6 mL). EDC (60 mg, 0.31 mmol) and DMAP (38 mg, 0.31 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and KO.sup.tBu (35 mg, 0.31 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (49 mg, 64%) as a white solid.

[1307] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.05-7.95 (m, 1H), 7.83 (d, 1H), 7.69 (dd, 1H), 7.42 (d, 1H), 7.00 (dd, 1H), 6.83 (dd, 1H), 6.78-6.64 (m, 2H), 3.88 (s, 3H), 3.41 (s, 2H), 2.97 (ddd, 1H), 2.41 (s, 3H), 1.08 (d, 6H).

[1308] LCMS: m/z 491 (M+H).sup.+ (ES.sup.+); 489 (MH).sup. (ES.sup.).

Example 102: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((6-hydroxy-2-methylpyridin-3-yl)sulfonyl)acetamide, potassium salt

[1309] ##STR00356##

[1310] 6-Hydroxy-2-methylpyridine-3-sulfonamide (34 mg, 0.18 mmol) and 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (55 mg, 0.18 mmol) were stirred in DCM (6 mL). EDC (69 mg, 0.36 mmol) and DMAP (44 mg, 0.36 mmol) were added. The mixture was stirred overnight, diluted with DCM (5 mL) and washed with 1M HCl (aqueous, 3 mL). The organic phase was concentrated. The residue was dissolved in DMSO (0.5 mL) and K.sub.2CO.sub.3 (50 mg, 0.36 mmol) was added. The mixture was submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1), followed by a second purification with the same method to afford the title compound (15 mg, 18%) as a white solid.

[1311] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.08 (d, 1H), 7.99 (d, 1H), 7.02 (dd, 1H), 6.88 (dd, 1H), 6.78-6.66 (m, 2H), 6.30 (d, 1H), 3.91 (s, 3H), 3.44 (s, 2H), 3.09-2.91 (m, 1H), 2.57 (s, 3H), 1.13 (d, 6H).

[1312] LCMS: m/z 474 (M+H).sup.+ (ES.sup.+); 472 (MH).sup. (ES.sup.).

Example 103: 2-Fluoro-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl) phenyl)-N-((4-(2-hydroxypropan-2-yl)furan-2-yl)sulfonyl)acetamide

[1313] ##STR00357##

[1314] To a solution of 2-fluoro-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A14) (50 mg, 155.61 mol, 1 eq) in DMF (1 mL) was added CDI (38 mg, 233.41 mol, 1.5 eq). The reaction mixture was stirred at 20 C. for 0.5 hour. Then to the above mixture was added a solution of 4-(2-hydroxypropan-2-yl)furan-2-sulfonamide (Intermediate P27) (32 mg, 155.61 mol, 1 eq) and NaH (9 mg, 233.41 mol, 60 wt % in mineral oil, 1.5 eq) in DMF (1 mL), which had been stirred at 20 C. for 0.5 hour. After addition, the resulting mixture was stirred at 20 C. for another 1 hour. The reaction mixture was quenched with water (0.1 mL) and filtered. The filtrate was purified by prep-HPLC (column: Phenomenex luna C18, 150 mm*25 mm*10 m; mobile phase [A: water (0.1% TFA); B: MeCN]; B %: 37%-67%, 10 min) to give the title compound (28.27 mg, 29% yield, 99% purity on HPLC, TFA salt) as a yellow solid.

[1315] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.22 (d, 1H), 7.79 (s, 1H), 7.35 (dd, 1H), 7.23 (s, 1H), 7.01 (d, 1H), 6.90 (d, 1H), 6.77 (s, 1H), 5.84 (d, 1H), 3.89 (s, 3H), 2.88-2.85 (m, 1H), 1.36 (s, 6H), 1.16 (d, 3H) and 0.89 (d, 3H).

[1316] LCMS: m/z 509.2 (M+H).sup.+ (ES.sup.+).

Example 104: 2-Fluoro-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl) phenyl)-N-((4-(2-hydroxypropan-2-yl)thiophen-2-yl)sulfonyl)acetamide

[1317] ##STR00358##

[1318] To a solution of 2-fluoro-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A14) (60 mg, 186.73 mol, 1 eq) in DMF (1 mL) was added CDI (45 mg, 280.10 mol, 1.5 eq). The reaction mixture was stirred at 20 C. for 0.5 hour. Then to the above mixture was added a solution of 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate P14) (41 mg, 186.73 mol, 1 eq) and NaH (11 mg, 280.10 mol, 60 wt % in mineral oil, 1.5 eq) in DMF (1 mL), which had been stirred at 20 C. for 0.5 hour. After addition, the resulting mixture was stirred at 20 C. for another 1 hour. The reaction mixture was quenched with water (0.1 mL) and filtered. The filtrate was purified by prep-HPLC (column: Xtimate C18, 150 mm*25 mm*5 m; mobile phase [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 10%-40%, 10 min) to give the title compound (52.87 mg, 52% yield, 99% purity on HPLC, ammonium salt) as a white solid.

[1319] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) 8.16 (d, 1H), 7.45 (s, 1H), 7.33 (s, 1H), 7.19 (d, 1H), 7.07 (s, 1H), 6.99-6.96 (m, 1H), 6.89 (d, 1H), 5.45 (d, 1H), 3.85 (s, 3H), 3.13-3.08 (m, 1H), 1.36 (s, 6H), 1.05 (d, 3H) and 0.76 (d, 3H).

[1320] LCMS: m/z 525.2 (M+H).sup.+ (ES.sup.+).

Example 105: N-((5-(2-Hydroxypropan-2-yl)thiazol-2-yl)sulfonyl)-2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetamide

[1321] ##STR00359##

[1322] To a solution of 5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide (Intermediate P15) (80 mg, 359.90 mol, 1 eq), 2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-H-inden-4-yl)acetic acid (Intermediate A2, Step F, non salt form) (112 mg, 395.89 mol, 1.1 eq) and DMAP (66 mg, 539.85 mol, 1.5 eq) in DMF (1.5 mL) was added EDC (104 mg, 539.85 mol, 1.5 eq) at 25 C. The reaction mixture was stirred at 25 C. for 1 hour, and then was purified by prep-HPLC (Column: Phenomenex Synergi C18, 150 mm*25 mm*10 m; mobile phase [A: water (0.1% TFA v/v), B: MeCN]; B %: 35%-65%,10 min) to give the title compound (104 mg, 59% yield, 99.7% purity on LCMS) as a white solid.

[1323] .sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O) 8.12 (d, 1H), 7.96 (d, 1H), 7.19 (d, 1H), 6.98 (d, 1H), 6.63 (d, 1H), 6.58 (s, 1H), 3.87 (s, 3H), 3.54 (s, 2H), 2.87 (t, 2H), 2.60 (t, 2H), 2.01-1.92 (m, 2H) and 1.54 (s, 6H).

[1324] LCMS: m/z 488.1 (M+H).sup.+ (ES.sup.+).

Example 106: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((5-(2-hydroxypropan-2-yl)thiazol-2-yl)sulfonyl)acetamide

[1325] ##STR00360##

[1326] To a solution of 5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide (Intermediate P5) (80 mg, 359.90 mol, 1 eq), 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (120 mg, 395.89 mol, 1.1 eq) and DMAP (66 mg, 539.85 mol, 1.5 eq) in DMF (1.5 mL) was added EDC (103 mg, 539.85 mol, 1.5 eq) at 25 C. The reaction mixture was stirred at 25 C. for 1 hour, and then purified by prep-HPLC (Column: Phenomenex Luna C18, 150 mm*25 mm*10 m; mobile phase [A: water (0.1% TFA v/v); B: MeCN]; B %: 40%-70%, 10 min) to give the title compound (97 mg, 52% yield, 98.2% purity on LCMS) as a white solid.

[1327] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.82 (br s, 1H), 8.14 (d, 1H), 7.98 (s, 1H), 7.20 (dd, 1H), 6.88 (dd, 1H), 6.62-6.60 (m, 2H), 3.89 (s, 3H), 3.56 (s, 2H), 2.79-2.72 (m, 1H), 1.54 (s, 6H) and 1.05 (d, 6H).

[1328] LCMS: m/z 508.2 (M+H).sup.+ (ES.sup.+).

Example 107: N-((2-(2-Hydroxypropan-2-yl)thiazol-5-yl)sulfonyl)-2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetamide

[1329] ##STR00361##

[1330] To a solution of 2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide (Intermediate P16) (80 mg, 359.90 mol, 1 eq), 2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid (Intermediate A2, Step F, non salt form) (112 mg, 395.89 mol, 1.1 eq) and DMAP (65 mg, 539.85 mol, 1.5 eq) in DMF (2 mL) was added EDC (103 mg, 539.85 mol, 1.5 eq) at 25 C. The reaction mixture was stirred at 25 C. for 1 hour, and then concentrated in vacuo. The residue was purified by prep-HPLC (Column: Phenomenex Luna C18, 150 mm*25 mm*10 m; mobile phase [A: water (0.1% TFA v/v), B: MeCN]; B %: 35%-65%, 10 min) to give the title compound (77.65 mg, 35% yield, 98.3% purity on LCMS, TFA salt) as a white solid.

[1331] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.61 (br s, 1H), 8.27 (s, 1H), 8.06 (d, 1H), 7.21 (d, 1H), 7.00 (d, 1H), 6.62 (dd, 1H), 6.54 (s, 1H), 3.85 (s, 3H), 3.51 (s, 2H), 2.89 (t, 2H), 2.59 (t, 2H), 2.00-1.93 (m, 2H) and 1.52 (s, 6H).

[1332] LCMS: m/z 488.2 (M+H).sup.+ (ES.sup.+).

Example 108: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((2-(2-hydroxypropan-2-yl)thiazol-5-yl)sulfonyl)acetamide

[1333] ##STR00362##

[1334] To a solution of 2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide (Intermediate P16) (80 mg, 359.90 mol, 1 eq), 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (120 mg, 395.89 mol, 1.1 eq) and DMAP (65 mg, 539.85 mol, 1.5 eq) in DMF (2 mL) was added EDC (103 mg, 539.85 mol, 1.5 eq) at 25 C. The reaction mixture was stirred at 25 C. for 1 hour, and then concentrated in vacuo. The residue was purified by prep-HPLC (Column: Phenomenex Luna C18, 150 mm*25 mm*5 m; mobile phase [A: water (0.075% TFA v/v), B: MeCN]; B %: 38%-68%, 9 min) to give the title compound (51.76 mg, 23% yield, 99.3% purity on LCMS, TFA salt) as a white solid.

[1335] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.27-8.25 (m, 2H), 7.14 (dd, 1H), 6.97-6.96 (m, 2H), 6.78 (dd, 1H), 4.08 (s, 3H), 3.63 (s, 2H), 2.94-2.88 (m, 1H), 1.68 (s, 6H) and 1.18 (d, 6H).

[1336] LCMS: m/z 508.1 (M+H).sup.+ (ES.sup.+).

Example 109: 2-(2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)-N-((1-cyclopropyl-1H-imidazol-4-yl)sulfonyl)acetamide

[1337] ##STR00363##

[1338] A solution (A) of 1-cyclopropyl-1H-imidazole-4-sulfonamide (Intermediate P4) (7 mg, 36.20 mol, 1.2 eq) and NaH (1 mg, 36.20 mol, 60 wt % in mineral oil, 1.2 eq) in DMF (0.2 mL) was stirred at 25 C. for 30 minutes. To another solution (B) of 2-(2-(2-cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid (Intermediate A7) (9 mg, 30.17 mol, 1 eq) and TEA (6 mg, 60.34 mol, 2 eq) in THF (0.2 mL) was added isobutyl carbonochloridate (5 mg, 37.71 mol, 1.25 eq) at 0 C., and then the solution (B) was stirred for 30 minutes. The solution (B) was filtered and the filtrate was added into the solution (A). The resulting mixture was stirred at 25 C. for 30 minutes, and then concentrated in vacuo to remove most of THF. The residue was purified by prep-HPLC (Column: Waters Xbridge, 150 mm*25 mm*5 m; mobile phase [A: water (0.05% ammonium hydroxide v/v), B: MeCN]; B %: 5%-35%,10 min) to give the title compound (5.65 mg, 40% yield, 100% purity on LCMS) as a white solid.

[1339] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.68 (s, 1H), 7.65-7.55 (m, 3H), 7.38 (d, 1H), 7.08 (d, 1H), 6.71 (d, 1H), 3.56 (s, 2H), 3.43-3.41 (m, 1H), 2.96-2.94 (m, 1H) and 1.11-1.01 (m, 10H).

[1340] LCMS: m/z 468.3 (M+H).sup.+ (ES.sup.+).

Example 110: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((4-isopropylphenyl)sulfonyl)acetamide

[1341] ##STR00364##

[1342] A solution of 4-isopropylbenzenesulfonamide (0.020 g, 0.1 mmol), 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) (0.030 g, 0.1 mmol), EDC (0.038 g, 0.200 mmol) and DMAP (0.024 g, 0.200 mmol) in DMF (1.4 mL) was shaken in a 96 well plate at room temperature for 16 hours at 900 rpm. The crude product was purified by acidic prep without workup (50-80% MeCN in water) to afford the title compound (23 mg, 48%) as a white solid.

[1343] LCMS m/z 507.4 (M+Na).sup.+ (ES.sup.+).

[1344] .sup.1H NMR (DMSO-d.sub.6) 12.17 (s, 1H), 8.03 (d, J=5.2 Hz, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 7.14 (dd, J=10.5, 2.8 Hz, 1H), 6.84 (dd, J=8.8, 2.7 Hz, 1H), 6.59 (br s, 1H), 6.54 (dd, J=5.2, 1.4 Hz, 1H), 3.88 (s, 3H), 3.80-3.75 (m, 1H), 3.46 (s, 2H), 2.70-2.64 (m, 1H), 1.22 (d, J=6.9 Hz, 6H), 0.95 (d, J=6.7 Hz, 6H).

Example 111: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-(phenylsulfonyl)acetamide

[1345] ##STR00365##

[1346] Prepared according to the general procedure of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((4-isopropylphenyl)sulfonyl)acetamide (Example 110) from 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) and benzenesulfonamide to afford the title compound (23 mg, 51%) as a white solid.

[1347] LCMS m/z 465.3 (M+Na).sup.+ (ES.sup.+).

[1348] .sup.1H NMR (DMSO-d6) 12.25 (s, 1H), 8.03 (d, J=5.1 Hz, 1H), 7.93-7.88 (m, 2H), 7.77-7.71 (m, 1H), 7.69-7.62 (m, 2H), 7.15 (dd, J=10.5, 2.8 Hz, 1H), 6.84 (dd, J=8.9, 2.8 Hz, 1H), 6.58-6.52 (m, 2H), 3.87 (s, 3H), 3.48 (s, 2H), 2.74-2.66 (m, 1H), 0.98 (d, J=6.7 Hz, 6H).

Example 112: 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-tosylacetamide

[1349] ##STR00366##

[1350] Prepared according to the general procedure of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-N-((4-isopropylphenyl)sulfonyl)acetamide (Example 110) from 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid (Intermediate A1, non salt form) and 4-methylbenzenesulfonamide to afford the title compound (21 mg, 46%) as a white solid.

[1351] LCMS m/z 455.4 (MH).sup. (ES.sup.).

[1352] .sup.1H NMR (DMSO-d6) 12.16 (s, 1H), 8.03 (d, J=5.4 Hz, 1H), 7.79 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.15 (dd, J=10.5, 2.8 Hz, 1H), 6.84 (dd, J=8.9, 2.8 Hz, 1H), 6.61-6.47 (m, 2H), 3.87 (s, 3H), 3.46 (s, 2H), 2.78-2.66 (m, 1H), 2.41 (s, 3H), 0.99 (d, J=6.7 Hz, 6H).

[1353] The compounds of examples 113-209 were synthesised by methods analogous to those outlined above.

TABLE-US-00008 TABLE 2 UPLC/MS and MS data Retention Ex Structure and Name time (min)* MS MW 113 [00367] 1.66 493.27 (M + H).sup.+ (ES.sup.+); 491.27 (M H).sup. (ES.sup.). 492.5 114 [00368] 1.69 488.34 (M + H).sup.+ (ES.sup.+); 486.32 (M H).sup. (ES.sup.). 487.6 115 [00369] 1.60 483.28 (M + H).sup.+ (ES.sup.+); 481.25 (M H).sup. (ES.sup.). 482.5 116 [00370] 1.73 483.29 (M + H).sup.+ (ES.sup.+); 481.27 (M H).sup. (ES.sup.). 482.5 117 [00371] 1.75 471.30 (M + H).sup.+ (ES.sup.+); 469.31 (M H).sup. (ES.sup.). 470.6 118 [00372] 1.67 499.32 (M + H).sup.+ (ES.sup.+); 497.30 (M H).sup. (ES.sup.). 498.6 119 [00373] 1.63 473.30 (M + H).sup.+ (ES.sup.+); 471.28 (M H).sup. (ES.sup.). 472.5 120 [00374] 1.67 475.29 (M + H).sup.+ (ES.sup.+); 473.25 (M H).sup. (ES.sup.). 474.5 121 [00375] 1.72 477.25 (M + H).sup.+ (ES.sup.+); 475.25 (M H).sup. (ES.sup.). 476.6 122 [00376] 1.73 471.3 (M + H).sup.+ (ES.sup.+); 469.3 (M H).sup. (ES.sup.). 470.56 123 [00377] 1.78 483.3 (M + H).sup.+ (ES.sup.+); 481.3 (M H).sup. (ES.sup.). 482.57 124 [00378] 1.53 485.3 (M + H).sup.+ (ES.sup.+); 483.3 (M H).sup. (ES.sup.). 484.54 125 [00379] 1.72 475.3 (M + H).sup.+ (ES.sup.+); 473.3 (M H).sup. (ES.sup.). 474.52 *Analytical UPLC/MS was carried out using a Waters Acquity CSH C18, 1.7 m, 2.1 30 mm column eluting with a gradient of 0.1% formic acid in MeCN in 0.1% formic acid in water. The gradient is structured with a starting point of 5% MeCN held from 0.0-0.11 minutes. The gradient from 5-95% occurs between 0.11-2.15 minutes with a flush from 2.15-2.56 minutes. A column re-equilibration to 5% MeCN is from 2.56-2.83 minutes. Temperature: 40 C. Flow rate 0.77 mL min.sup.-1. UV spectra of the eluted peaks were measured using an Acquity PDA and mass spectra were recorded using an Acquity QDa detector with ESI pos/neg switching.

TABLE-US-00009 TABLE 3 .sup.1H NMR and MS data Ex Structure and Name 1H NMR spectrum MS MW 126 [00380] .sup.1H NMR (DMSO-d6) 12.34 (s, 1H), 8.61 (d, J = 1.9 Hz, 1H), 8.23 (d, J = 8.2 Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 5.1 Hz, 1H), 7.88 (dd, J = 8.6, 1.9 Hz, 1H), 7.78-7.73 (m, 1H), 7.73-7.68 (m, 1H), 7.10 (dd, J = 10.5, 2.8 Hz, 1H), 6.81 (dd, J = 8.9, 2.7 Hz, 1H), 6.56-6.50 (m, 2H), 3.82 (s, 3H), 3.49 (s, 2H), 2.70-2.60 (m, 1H), 0.90 (d, J = 6.7 Hz, 6H). 493.3 (M + H)+ (ES.sup.+); 491.3 (M H).sup. (ES.sup.). 492.56 127 [00381] .sup.1H NMR (300 MHz, Methanol-d.sub.4) .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.24 (s, 1H), 8.00 (d, 1H), 7.57 (d, 1H), 7.46 (s, 1H), 7.32 (d, 1H), 7.02 (dd, 1H), 6.89 (dd, 1H), 6.78 (s, 1H), 6.72 (dd, 1H), 3.84 (s, 3H), 3.45 (s, 2H), 3.16-2.97 (m, 1H), 1.12 (d, 6H). m/z 516.0 (M + H).sup.+ (ES.sup.+); 514.0 (M H).sup. (ES.sup.). 515.57 128 [00382] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.10 (d, 1H), 8.04 (d, 1H), 7.48 (dd, 1H), 7.18 (d, 1H), 6.99 (dd, 1H), 6.84 (dd, 1H), 6.76-6.64 (m, 2H), 3.90 (s, 3H), 3.45 (s, 2H), 3.11-2.92 (m, 1H), 2.54 (s, 3H), 1.09 (d, 6H). m/z 535.0 (M + H).sup.+ (ES.sup.+); 533.0 (M H).sup. (ES.sup.). 535.43 129 [00383] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.04 (d, 1H), 7.85 (d, 1H), 7.44 (d, 1H), 7.37 (dd, 1H), 6.99 (dd, 1H), 6.83 (dd, 1H), 6.77-6.63 (m, 2H), 3.90 (s, 3H), 3.45 (s, 2H), 2.98 (dt, 1H), 2.57 (s, 3H), 1.09 (d, 6H). m/z 535.0 (M + H).sup.+ (ES.sup.+); 533.0 (M H).sup. (ES.sup.). 535.43 130 [00384] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.01 (d, 1H), 7.89-7.78 (m, 2H), 7.30 (d, 2H), 6.99 (dd, 1H), 6.83 (dd, 1H), 6.75 (s, 1H), 6.70 (dd, 1H), 3.90 (s, 3H), 3.41 (m, 4H), 3.10- 2.94 (m, 1H), 2.84 (t, 2H), 1.88 (s, 3H), 1.09 (d, 6H). m/z 528.0 (M + H).sup.+ (ES.sup.+); 526.0 (M H).sup. (ES.sup.). 527.61 131 [00385] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.09 (dd, 1H), 7.04 (dd, 1H), 6.91 (dd, 1H), 6.80-6.67 (m, 2H), 3.96 (s, 3H), 3.89 (s, 3H), 3.48 (s, 2H), 3.15-3.00 (m, 1H), 2.29 (s, 3H), 1.16 (d, 6H). m/z 522.0 (M + H ).sup.+ (ES.sup.+); 520.2 (M H).sup. (ES.sup.). 521.58 132 [00386] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 7.99 (d, 1H), 7.89 (d, 2H), 7.73 (d, 2H), 6.99 (dd, 1H), 6.82 (dd, 1H), 6.78-6.65 (m, 2H), 3.87 (s, 3H), 3.42 (s, 2H), 3.09- 2.93 (m, 1H), 2.24 (s, 3H), 1.08 (d, 6H). m/z 500.0 (M + H).sup.+ (ES.sup.+); 498.2 (M H).sup. (ES.sup.). 499.56 133 [00387] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 7.98 (d, 1H), 7.86 (s, 1H), 7.79 (s, 1H), 7.41 (m, 2H), 7.03-6.94 (m, 1H), 6.82 (d, 1H), 6.77-6.64 (m, 2H), 4.40 (s, 2H), 3.88 (s, 3H), 3.41 (s, 2H), 3.02 (m, 1H), 1.97 (s, 3H), 1.07 (d, 6H). m/z 514.0 (M + H).sup.+ (ES.sup.+); 512.2 (M H).sup. (ES.sup.). 513.58 134 [00388] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.03 (dd, 1H), 7.95 (d, 1H), 7.29 (d, 1H), 7.23 (dd, 1H), 6.97 (dd, 1H), 6.83 (dd, 1H), 6.,74 (dd, 1H), 6.68 (dd, 1H), 3.90 (s, 3H), 3.45 (s, 2H), 2.97 (dd, 1H), 2.62 (s, 3H), 1.67 (s, 3H), 1.60 (s, 3H), 1.06 (d, 6H). m/z 517.0 (M + H).sup.+ (ES.sup.+); 515.2 (M H).sup. (ES.sup.). 516.6 135 [00389] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.03 (dd, 1H), 7.78-7.66 (m, 2H), 7.56 (dd, 1H), 7.01 (dd, 1H), 6.83 (dd, 1H), 6.75- 6.65 (m, 2H), 3.89 (s, 3H), 3.42 (s, 2H), 2.98 (td, 1H), 1.10 (d, 6H). m/z 495.0 (M + H).sup.+ (ES.sup.+); 493.0 (M H).sup. (ES.sup.). 494.94 136 [00390] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.04 (dd, 1H), 7.93 (d, 1H), 7.30-7.25 (m, 1H), 7.21 (dd, 1H), 6.99 (dd, 1H), 6.83 (dd, 1H), 6.74-6.64 (m, 2H), 3.90 (s, 3H), 3.45 (s, 2H), 3.01 (m, 1H), 2.58 (s, 3H), 1.09 (d, 6H). m/z 491.0 (M + H).sup.+ (ES.sup.+); 489.2 (M H).sup. (ES.sup.). 490.97 137 [00391] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.72 (dd, 1H), 8.11-8.02 (m, 1H), 8.02-7.93 (m, 2H), 6.99 (dd, 1H), 6.88 (dd, 1H), 6.76 (dd, 1H), 6.70 (dd, 1H), 3.92 (s, 3H), 3.47 (s, 2H), 3.12-2.99 (m, 1H), 1.56 (s, 6H), 1.08 (d, 6H). m/z 502.0 (M + H).sup.+ (ES.sup.+); 500.2 (M H).sup. (ES.sup.). 501.57 138 [00392] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.08 (dd, 1H), 7.02 (dd, 1H), 6.89 (dd, 1H), 6.79-6.67 (m, 2H), 3.88 (s, 3H), 3.47 (s, 2H), 3.14-2.98 (m, 1H), 2.24 (s, 3H), 1.14 (d, 6H). m/z 508.0 (M + H).sup.+ (ES.sup.+); 506.2 (M H).sup. (ES.sup.). 507.56 139 [00393] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.05 (dd, 1H), 7.76 (d, 1H), 7.57-7.48 (m, 1H), 7.00 (dd, 1H), 6.83 (dd, 1H), 6.74- 6.64 (m, 2H), 3.91 (s, 3H), 3.45 (s, 2H), 3.08-2.90 (m, 1H), 2.55-2.49 (m, 3H), 1.10 (d, 6H). m/z 553.0 (M + H).sup.+ (ES.sup.+); 551.0 (M H).sup. (ES.sup.). 553.42 140 [00394] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.20 (d, 1H), 8.05 (dd, 1H), 7.93 (d, 1H), 7.83 (dd, 1H), 6.99 (dd, 1H), 6.86 (dd, 1H), 6.74-6.65 (m, 2H), 3.90 (s, 3H), 3.45 (s, 2H), 3.01 (d, 1H), 1.08 (d, 6H). m/z 589.0 (M + H).sup.+ (ES.sup.+); 587.0 (M H).sup. (ES.sup.). 589.4 141 [00395] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.28 (d, 1H), 8.08 (dd, 1H), 8.02 (dd, 1H), 7.70 (d, 1H), 6.99 (dd, 1H), 6.84 (dd, 1H), 6.75-6.67 (m, 2H), 3.89 (d, 3H), 3.41 (s, 2H), 2.92 (d, 1H), 1.06 (d, 6H). m/z 545.0 (M + H).sup.+ (ES.sup.+); 543.0 (M H).sup. (ES.sup.). 544.95 142 [00396] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.54- 8.44 (m, 2H), 8.02 (s, 1H), 7.83 (dt, 1H), 7.41 (dd, 1H), 7.04 (dd, 1H), 6.76 (dd, 1H), 3.42 (s, 2H), 3.07 (dd, 1H), 1.59 (s, 6H), 1.13 (d, 6H). m/z 478.0 (M + H).sup.+ (ES.sup.+); 476.2 (M H).sup. (ES.sup.). 477.57 143 [00397] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.55- 8.43 (m, 2H), 7.83 (dt, 1H), 7.63 (s, 1H), 7.45 (dd, 1H), 7.04 (dd, 1H), 6.76 (dd, 1H), 3.46 (s, 2H), 3.10 (dd, 1H), 1.62 (s, 6H), 1.16 (d, 6H). m/z 478.0 (M + H).sup.+ (ES.sup.+); 476.0 (M H).sup. (ES.sup.). 477.57 144 [00398] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.01 (dd, 1H), 7.71 (d, 1H), 7.61 (d, 1H), 7.06 (dd, 1H), 6.81-6.72 (m, 2H), 6.68 (dd, 1H), 3.90 (s, 3H), 3.48 (s, 2H), 3.07 (s, 3H), 3.03-2.85 (m, 1H), 1.51 (s, 6H), 1.13 (d, 6H). m/z 521.0 (M + H).sup.+ (ES.sup.+); 519.2 (M H).sup. (ES.sup.). 520.63 145 [00399] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.03 (dd, 1H), 7.66-7.59 (m, 2H), 7.39 (d, 1H), 6.98 (dd, 1H), 6.71 (ddd, 2H), 3.92 (s, 3H), 3.44 (s, 2H), 3.13-3.00 (m, 1H), 1.51 (s, 6H), 1.12 (d, 6H). m/z 507.0 (M + H).sup.+ (ES.sup.+); 505.2 (M H).sup. (ES.sup.). 506.61 146 [00400] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.04 (dd, 2H), 7.01 (dd, 1H), 6.81-6.67 (m, 3H), 6.42 (s, 1H), 3.89 (s, 3H), 3.47 (s, 2H), 3.09 (s, 6H), 2.98 (s, 3H), 2.88 (m, 1H), 2.61 (s, 3H), 1.08 (d, 6H). m/z 514.2 (M + H).sup.+ (ES.sup.+); 512.2 (M H).sup. (ES.sup.). 513.63 147 [00401] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.15 (d, 1 H), 7.62 (d, 1 H), 7.36 (s, 1 H), 7.00 (s, 1 H), 6.92 (s, 1 H), 3.92 (s, 3 H), 3.70 (s, 3 H), 3.23 (s, 2 H), 2.87 (p, 1 H), 1.50 (s, 6 H), 1.17 (d, 6 H). m/z 493.2 (M + H).sup.+ (ES.sup.+); 491.2 (M H).sup. (ES.sup.). 492.61 148 [00402] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.17 (d, 1H), 8.02 (d, 1H), 7.61 (d, 1H), 7.56 (dd, 1H), 7.36 (d, 1H), 7.03 (dd, 1H), 6.78 (dd, 1H), 3.80 (s, 3H), 3.43 (s, 2H), 3.16-2.99 (m, 1H), 1.50 (s, 6H), 1.13 (d, 6H). m/z 507.0 (M + H).sup.+ (ES.sup.+); 505.2 (M H).sup. (ES.sup.). 506.61 149 [00403] .sup.1H NMR (299 MHz, Methanol-d.sub.4) 8.23 (t, 1H), 8.06 (d, 1H), 7.04-6.91 (m, 2H), 6.87 (dt, 1H), 6.75- 6.65 (m, 2H), 3.91 (d, 3H), 3.45 (s, 2H), 3.14-2.93 (m, 1H), 1.54 (d, 6H), 1.10 (d, 6H). m/z 537.2 (M + H).sup.+ (ES.sup.+); 535.2 (M H).sup. (ES.sup.). 536.57 150 [00404] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 7.99 (dd, 1H), 7.80 (d, 1H), 7.47 (d, 1H), 7.01 (dd, 1H), 6.88 (dd, 1H), 6.82-6.76 (m, 1H), 6.72 (dd, 1H), 5.39 (s, 1H), 5.03 (t, 1H), 3.87 (s, 3H), 3.44 (s, 2H), 3.04 (m, 1H), 2.10 (s, 3H), 1.11 (d, 6H). m/z 489.0 (M + H).sup.+ (ES.sup.+); 487.2 (M H).sup. (ES.sup.). 488.59 151 [00405] .sup.1H NMR (299 MHz, Methanol-d.sub.4) 8.02 (d, 1H), 7.83 (d, 1H), 7.01-6.92 (m, 2H), 6.85 (dd, 2H), 6.77- 6.63 (m, 2H), 3.89 (s, 3H), 3.44 (s, 2H), 2.99 (m, 1H), 2.56 (s, 3H), 1.89 (m, 1H), 1.07 (d, 6H), 1.05- 0.94 (m, 2H), 0.71 (m, 2H). m/z 497.2 (M + H).sup.+ (ES.sup.+); 495.2 (M H).sup. (ES.sup.). 496.60 152 [00406] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.07 (dd, 1H), 7.00 (dd, 1H), 6.88 (dd, 1H), 6.78 (dd, 1H), 6.72 (dd, 1H), 4.50 (m, 1H), 3.91 (s, 3H), 3.43 (s, 2H), 3.05- 2.91 (m, 1H), 2.48 (s, 3H), 2.37 (s, 3H), 1.39 (d, 6H), 1.07 (d, 6H). m/z 503.2 (M + H).sup.+ (ES.sup.+); 501.2 (M H).sup. (ES.sup.). 502.61 153 [00407] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.05 (dd, 1H), 7.45 (d, 1H), 7.08 (d, 1H), 6.98 (dd, 1H), 6.84 (dd, 1H), 6.76 (m, 3H), 3.88 (s, 3H), 3.47 (s, 2H), 3.13 (m, 1H), 2.88 (s, 6H), 2.48 (s, 3H), 1.08 (d, 6H). m/z 500.2 (M + H).sup.+ (ES.sup.+); 498.2 (M H).sup. (ES.sup.). 499.60 154 [00408] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.13 (d, 1 H), 7.83 (d, 1 H), 7.54 (d, 1 H), 6.93 (dd, 1 H), 6.85 (s, 1 H), 5.39 (s, 1 H), 5.05 (s, 1 H), 3.90 (s, 3 H), 3.69 (s, 3 H), 3.27 (s, 2 H), 2.87 (p, 1 H), 2.09 (s, 3 H), 1.16 (d, 6 H). m/z 475.0 (M + H).sup.+ (ES.sup.+); 473.2 (M H).sup. (ES.sup.). 474.59 155 [00409] .sup.1H NMR (299 MHz, Methanol-d.sub.4) 8.02 (d, 1H), 7.60 (s, 1H), 6.99 (dd, 1H), 6.81- 6.64 (m, 3H), 6.40 (s, 1H), 3.88 (d, 3H), 3.46 (s, 2H), 3.20- 3.12 (m, 1H), 2.88 (s, 3H), 2.53 (s, 3H), 2.06 (s, 3H), 1.09 (dd, 6H). m/z 500.2 (M + H).sup.+ (ES.sup.+); 498.2 (M H).sup. (ES.sup.). 499.60 156 [00410] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.06 (dd, 1H), 7.86 (t, 1H), 7.04-6.95 (m, 2H), 6.95-6.84 (m, 1H), 6.77-6.65 (m, 2H), 3.90 (s, 3H), 3.45 (s, 2H), 3.18 (m, 1H), 3.04 (m, 1H), 1.25 (d, 6H), 1.11 (d, 6H). m/z 521.2 (M + H).sup.+ (ES.sup.+); 519.2 (M H).sup. (ES.sup.). 520.57 157 [00411] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.03 (dd, 1H), 7.88 (d, 1H), 7.16-7.03 (m, 2H), 6.97 (dd, 1H), 6.83 (dd, 1H), 6.75 (dd, 1H), 6.69 (dd, 1H), 3.90 (s, 3H), 3.45 (s, 2H), 3.06- 2.94 (m, 1H), 2.89 (m, 1H), 2.59 (s, 3H), 1.23 (d, 6H), 1.06 (d, 6H). m/z 499.2 (M + H).sup.+ (ES.sup.+); 497.2 (M H).sup. (ES.sup.). 498.61 158 [00412] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 7.63 (d, 1H), 7.37 (d, 1H), 7.27 (dd, 1H), 7.02 (dd, 1H), 6.73 (dd, 1H), 6.46-6.38 (m, 2H), 3.48 (s, 2H), 3.13-2.99 (m, 1H), 1.50 (s, 6H), 1.12 (d, 6H). m/z 475.0 (M + H 18).sup.+ (ES.sup.+); 491.2 (M H).sup. (ES.sup.). 492.58 159 [00413] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.02 (dd, 1H), 7.46 (s, 1H), 7.02 (dd, 1H), 6.91 (dd, 1H), 6.80 (dd, 1H), 6.73 (dd, 1H), 3.90 (s, 3H), 3.43 (s, 2H), 3.17-3.00 (m, 1H), 2.58 (s, 3H), 1.53 (s, 6H), 1.13 (d, 6H). m/z 521.2 (M + H).sup.+ (ES.sup.+); 519.2 (M H).sup. (ES.sup.). 520.63 160 [00414] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.08 (dd, 1H), 7.02 (dd, 1H), 6.85 (dd, 1H), 6.77 (dd, 1H), 6.72 (dd, 1H), 6.65 (s, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.45 (s, 2H), 3.14-2.98 (m, 1H), 1.50 (s, 6H), 1.13 (d, 6H). m/z 505.2 (M + H).sup.+ (ES.sup.+); 503.2 (M H).sup. (ES.sup.). 504.58 161 [00415] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.11- 8.05 (m, 1H), 6.99 (dd, 1H), 6.92 (dd, 1H), 6.81-6.74 (m, 1H), 6.74-6.60 (m, 3H), 3.91 (s, 3H), 3.48 (s, 2H), 3.17- 3.06 (m, 1H), 3.04- 2.96 (s, 6H), 1.11 (d, 6H). m/z 556.0 (M + H).sup.+ (ES.sup.+); 554.2 (M H).sup. (ES.sup.). 554.46 162 [00416] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.56 (s, 1H), 8.04 (d, 1H), 6.99 (dd, 1H), 6.85 (d, 1H), 6.74 (s, 1H), 6.69 (dd, 1H), 6.47 (s, 1H), 3.89 (s, 3H), 3.43 (d, 2H), 3.10 (s, 6H), 3.01 (m, 1H), 2.51 (s, 3H), 1.10 (d, 6H). m/z 501.4 (M + H).sup.+ (ES.sup.+); 499.4 (M H).sup. (ES.sup.). 500.59 163 [00417] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.02 (dd, 1 H), 7.79 (d, 1 H), 7.46 (d, 1 H), 7.12 (dd, 1 H), 7.02 (dd, 1 H), 5.36 (t, 1 H), 5.02 (t, 1 H), 3.87 (s, 3 H), 3.85 (s, 3 H), 3.48 (s, 2 H), 3.08-2.96 (m, 1 H), 2.12-2.00 (m, 3 H), 1.25 (d, 6 H). m/z 475.0 (M + H).sup.+ (ES.sup.+); 473.2 (M H).sup. (ES.sup.). 474.59 164 [00418] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.02 (dd, 1H), 7.92 (d, 1H), 7.40-7.28 (m, 2H), 6.97 (dd, 1H), 6.83 (dd, 1H), 6.74 (d, 1H), 6.68 (dd, 1H), 5.42 (dd, 1H), 5.16-5.09 (m, 1H), 3.88 (s, 3H), 3.45 (s, 2H), 3.01 (m, 1H), 2.61 (s, 3H), 2.14 (dd, 3H), 1.08 (d, 6H). m/z 497.2 (M + H).sup.+ (ES.sup.+); 495.2 (M H).sup. (ES.sup.). 496.60 165 [00419] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.06 (dd, 1H), 7.91 (t, 1H), 7.07-6.95 (m, 2H), 6.88 (dd, 1H), 6.75- 6.65 (m, 2H), 5.31- 5.23 (m, 2H), 3.90 (s, 3H), 3.45 (s, 2H), 3.10-2.97 (m, 1H), 2.11 (m, 3H), 1.12 (d, 6H). m/z 519.2 (M + H).sup.+ (ES.sup.+); 517.2 (M H).sup. (ES.sup.). 518.55 166 [00420] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.13 (t, 1H), 8.07 (dd, 1H), 7.21 (t, 1H), 7.00 (dd, 1H), 6.88 (dd, 1H), 6.76-6.67 (m, 2H), 3.91 (s, 3H), 3.44 (s, 2H), 3.04 (dd, 1H), 1.12 (d, 6H). m/z 558.0 (M + H).sup.+ (ES.sup.+); 556.0 (M H).sup. (ES.sup.). 557.38 167 [00421] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.13 (d, 1H), 8.02 (dd, 1H), 7.48 (dd, 1H), 7.22 (d, 1H), 6.98 (dd, 1H), 6.82 (dd, 1H), 6.75-6.65 (m, 2H), 3.89 (s, 3H), 3.45 (s, 2H), 3.02- 2.91 (m, 1H), 2.58 (s, 3H), 1.50 (s, 6H), 1.06 (d, 6H). m/z 515.2 (M + H).sup.+ (ES.sup.+); 513.2 (M H).sup. (ES.sup.). 514.61 168 [00422] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.09- 8.03 (m, 1H), 7.01 (dt, 1H), 6.88 (ddd, 1H), 6.77 (s, 1H), 6.72 (dd, 1H), 4.78 (m, 2H), 3.91 (s, 3H), 3.44 (s, 2H), 2.99 (m, 1H), 2.51-2.40 (d, 3H), 2.36 (s, 3H), 1.09 (dd, 6H). m/z 543.2 (M + H).sup.+ (ES.sup.+); 541.2 (M H).sup. (ES.sup.). 542.55 169 [00423] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.04 (d, 1H), 7.96 (s, 1H), 7.02 (dd, 1H), 6.85 (dd, 1H), 6.79-6.67 (m, 2H), 6.37-5.92 (m, 1H), 4.46 (m, 2H), 3.90 (s, 3H), 3.44 (s, 2H), 3.01 (m, 1H), 2.61 (s, 3H), 1.11 (d, 6H). m/z 511.2 (M + H).sup.+ (ES.sup.+); 509.2 (M H).sup. (ES.sup.). 510.53 170 [00424] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.50 (d, 1H), 8.16 (dd, 1H), 8.03 (dd, 1H), 7.59 (dd, 1H), 6.99 (dd, 1H), 6.87 (dd, 1H), 6.77-6.66 (m, 2H), 3.89 (s, 3H), 3.46 (s, 2H), 3.15- 2.94 (m, 1H), 1.52 (s, 6H), 1.07 (d, 6H). m/z 502.2 (M + H).sup.+ (ES.sup.+); 500.2 (M H).sup. (ES.sup.). 501.57 171 [00425] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.95 (dd, 1H), 8.24 (dd, 1H), 8.03 (dd, 1H), 7.74 (dd, 1H), 6.98 (dd, 1H), 6.82 (dd, 1H), 6.77-6.66 (m, 2H), 3.91 (s, 3H), 3.42 (s, 2H), 2.96 (m, 1H), 1.54 (s, 6H), 1.04 (d, 6H). m/z 502.2 (M + H).sup.+ (ES.sup.+); 500.2 (M H).sup. (ES.sup.). 501.57 172 [00426] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.06 (dd, 1H), 7.00 (dd, 1H), 6.89 (dd, 1H), 6.78 (dd, 1H), 6.72 (dd, 1H), 3.91 (s, 3H), 3.79 (d, 2H), 3.43 (m, 2H), 3.08- 2.94 (m, 1H), 2.46 (s, 3H), 2.35 (s, 3H), 2.13 (m, 1H), 1.10 (d, 6H), 0.89 (d, 6H). m/z 517.2 (M + H).sup.+ (ES.sup.+); 515.2 (M H).sup. (ES.sup.). 516.63 173 [00427] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.04 (dd, 1H), 7.91 (s, 1H), 7.01 (dd, 1H), 6.86 (dd, 1H), 6.78 (dd, 1H), 6.72 (dd, 1H), 4.40 (m, 1H), 3.90 (s, 3H), 3.43 (s, 2H), 3.01 (m, 1H), 2.37 (s, 3H), 1.44 (d, 6H), 1.09 (d, 6H). m/z 489.2 (M + H).sup.+ (ES.sup.+); 487.2 (M H).sup. (ES.sup.). 488.58 174 [00428] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.09- 8.01 (m, 1H), 7.43 (s, 1H), 7.03 (dd, 1H), 6.90 (dd, 1H), 6.83-6.77 (m, 1H), 6.72 (dd, 1H), 3.89 (s, 3H), 3.43 (s, 2H), 3.06 (m, 4H), 2.96 (s, 3H), 2.46 (s, 3H), 1.15 (d, 6H). m/z 534.1 (M + H).sup.+ (ES.sup.+); 532.2 (M H).sup. (ES.sup.). 533.63 175 [00429] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.06 (d, 1H), 7.00 (dd, 1H), 6.87 (dd, 1H), 6.77 (s, 1H), 6.72 (dd, 1H), 6.34-5.88 (m, 1H), 4.42 (m, 2H), 3.91 (s, 3H), 3.43 (s, 2H), 3.06-2.90 (m, 1H), 2.49 (s, 3H), 2.35 (s, 3H), 1.09 (d, 6H). m/z 525.2 (M + H).sup.+ (ES.sup.+); 523.2 (M H).sup. (ES.sup.). 524.56 176 [00430] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.01 (d, 1H), 7.81 (s, 1H), 7.02 (dd, 1H), 6.88 (dd, 1H), 6.80-6.67 (m, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.43 (s, 2H), 3.14-2.98 (m, 1H), 2.72 (s, 3H), 1.12 (d, 6H). m/z 521.0 (M + H).sup.+ (ES.sup.+); 519.2 (M H).sup. (ES.sup.). 520.59 177 [00431] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 7.99 (d, 1H), 7.83 (d, 2H), 7.40 (d, 1H), 7.31 (d, 2H), 6.83 (dd, 1H), 6.77-6.64 (m, 2H), 3.89 (s, 3H), 3.41 (s, 2H), 3.04 (m, 1H), 2.93-2.80 (m, 2H), 2.63 (m, 2H), 2.34 (d, 6H), 1.07 (d, 6H). m/z 514.2 (M + H).sup.+ (ES.sup.+); 512.2 (M H).sup. (ES.sup.). 513.63 178 [00432] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.21 (s, 1H), 8.05 (dd, 1H), 7.43 (d, 1H), 7.00 (dd, 1H), 6.84 (dd, 1H), 6.73-6.65 (m, 2H), 3.90 (s, 3H), 3.45 (s, 2H), 3.07-2.89 (m, 1H), 2.52 (s, 3H), 1.10 (d, 6H) m/z 571.0 (M + H).sup.+ (ES.sup.+); 569.0 (M H).sup. (ES.sup.). 569.87 179 [00433] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.02 (dd, 1H), 7.74-7.65 (m, 2H), 7.60-7.50 (m, 1H), 6.99 (dd, 1H), 6.84 (dd, 1H), 6.77 (dd, 1H), 6.71 (dd, 1H), 3.91 (s, 3H), 3.42 (s, 2H), 3.08-2.93 (m, 1H), 1.55 (s, 3H), 1.28- 1.20 (m, 2H), 1.08 (d, 6H), 0.76 (t, 3H). m/z 533.0 (M + H).sup.+ (ES.sup.+); 531.2 (M H).sup. (ES.sup.). 532.60 180 [00434] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 7.99 (dd, 1H), 7.90-7.81 (m, 2H), 7.51-7.39 (m, 2H), 6.98 (dd, 1H), 6.84 (dd, 1H), 6.76 (dd, 1H), 6.70 (dd, 1H), 3.88 (s, 3H), 3.55 (s, 2H), 3.41 (s, 2H), 3.10- 2.94 (m, 1H), 2.24 (s, 6H), 1.07 (d, 6H). m/z 500.2 (M + H).sup.+ (ES.sup.+); 498.2 (M H).sup. (ES.sup.). 499.60 181 [00435] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.60 (dd, 1H), 8.20-8.16 (m, 1H), 8.02 (dd, 1H), 7.66 (dd, 1H), 7.00 (dd, 1H), 6.84 (dd, 1H), 6.77-6.63 (m, 2H), 3.89 (s, 3H), 3.43 (s, 2H), 3.07-2.88 (m, 1H), 1.54 (s, 6H), 1.07 (d, 6H). m/z 502.0 (M + H).sup.+ (ES.sup.+); 500.2 (M H).sup. (ES.sup.). 501.57 182 [00436] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.04 (s, 1H), 8.03-8.00 (m, 1H), 7.70 (d, 1H), 7.63 (dd, 1H), 6.98 (dd, 1H), 6.82 (dd, 1H), 6.73-6.62 (m, 2H), 3.89 (s, 3H), 3.46 (s, 2H), 3.05-2.95 (m, 1H), 2.92 (s, 3H), 2.64 (s, 3H), 1.08 (d, 6H). m/z 514.2 (M + H).sup.+ (ES.sup.+); 512.2 (M H).sup. (ES.sup.). 513.58 183 [00437] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.03 (d, 1H), 7.57 (d, 1H), 7.52 (d, 1H), 7.03 (dd, 1H), 6.87 (dd, 1H), 6.79-6.77 (m, 1H), 6.73 (dd, 1H), 3.89 (s, 3H), 3.44 (s, 2H), 3.17- 2.86 (m, 1H), 1.13 (d, 6H). m/z 527.0 (M + H).sup.+ (ES.sup.+); 525.0 (M H).sup. (ES.sup.). 527.42 184 [00438] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.29 (s, 1H), 8.11-7.90 (m, 3H), 7.86-7.74 (m, 2H), 7.65 (s, 1H), 6.99 (dd, 1H), 6.83 (dd, 1H), 6.76-6.73 (m, 1H), 6.70 (dd, 1H), 3.86 (s, 3H), 3.44 (s, 2H), 3.08- 2.87 (m, 1H), 1.08 (d, 6H). m/z 510.0 (M + H).sup.+ (ES.sup.+); 508.2 (M H).sup. (ES.sup.). 509.55 185 [00439] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.46 (d, 1H), 8.04 (dd, 1H), 7.93 (dd, 1H), 7.82 (dd, 1H), 6.99 (dd, 1H), 6.86 (dd, 1H), 6.75 (dd, 1H), 6.70 (dd, 1H), 3.91 (s, 3H), 3.46 (s, 2H), 3.11-2.93 (m, 2H), 1.30 (d, 6H), 1.06 (d, 6H). m/z 486.0 (M + H).sup.+ (ES.sup.+); 484.2 (M H).sup. (ES.sup.). 485.57 186 [00440] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.46 (d, 2H), 7.94 (d, 1H), 7.43 (s, 1H), 7.36 (d, 1H), 7.29 (d, 2H), 7.09-6.96 (m, 1H), 6.79-6.67 (m, 1H), 3.44 (s, 2H), 3.06- 2.85 (m, 1H), 2.60 (s, 3H), 1.52 (s, 6H), 1.08 (d, 6H). m/z 485.20 (M + H).sup.+ (ES.sup.+); 483.20 (M H).sup. (ES.sup.). 484.59 187 [00441] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.06- 7.93 (m, 3H), 7.66- 7.55 (m, 2H), 7.06 (dd, 1H), 6.74 (dd, 1H), 6.64 (dd, 1H), 6.56 (dd, 1H), 4.07 (s, 2H), 3.91 (s, 3H), 3.48 (s, 2H), 2.88- 2.66 (m, 1H), 1.08 (d, 6H). m/z 482.0 (M + H).sup.+ (ES.sup.+); 480.2 (M H).sup. (ES.sup.). 481.54 188 [00442] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.13 (d, 1H), 7.36 (s, 1H), 7.06 (dd, 1H), 6.88 (dd, 1H), 6.78-6.69 (m, 2H), 3.92 (s, 3H), 3.59 (s, 2H), 3.07 (m, 1H), 2.53 (s, 6H), 1.18 (d, 6H). m/z 473.2 (M + H).sup.+ (ES.sup.+); 471.2 (M H).sup. (ES.sup.). 472.54 189 [00443] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.58 (dd, 1H), 7.90 (d, 1H), 7.86 (dd, 1H), 7.61 (dd, 1H), 7.38 (d, 1H), 7.33 (dd, 1H), 7.14 (d, 1H), 6.98 (d, 1H), 3.40 (s, 2H), 2.91 (t, 2H), 2.75 (t, 2H), 2.75 (s, 3H), 2.02 (m, 2H), 1.51 (s, 6H). m/z 488.2 (M H).sup. (ES.sup.). 489.59 190 [00444] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.02 (dd, 1H), 7.97-7.89 (m, 2H), 7.65-7.56 (m, 2H), 6.98 (dd, 1H), 6.84 (dd, 1H), 6.76 (dd, 1H), 6.70 (dd, 1H), 3.91 (s, 3H), 3.43 (s, 2H), 2.97 (m, 1H), 1.74 (s, 6H), 1.06 (d, 6H). m/z 510.2 (M + H).sup.+ (ES.sup.+); 508.2 (M H).sup. (ES.sup.). 509.60 191 [00445] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.27 (s, 1H), 8.11 (s, 1H), 8.05 (d, 1H), 7.01 (dd, 1H), 6.88 (dd, 1H), 6.79-6.66 (m, 2H), 3.89 (s, 3H), 3.49 (s, 2H), 3.16 (s, 6H), 3.03-2.92 (m, 1H), 1.16-1.10 (d, 6H). m/z 488.2 (M + H).sup.+ (ES.sup.+); 486.2 (M H).sup. (ES.sup.). 487.55 192 [00446] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.07 (dd, 1H), 7.71 (d, 1H), 7.02 (dd, 1H), 6.94 (dd, 1H), 6.81 (dd, 1H), 6.72 (dd, 1H), 6.62 (d, 1H), 3.92 (s, 3H), 3.45 (s, 2H), 3.11 (m, 1H), 2.70 (s, 2H), 2.01 (s, 6H), 1.58 (s, 6H), 1.15 (d, 6H). m/z 532.2 (M + H).sup.+ (ES.sup.+); 530.2 (M H).sup. (ES.sup.). 531.64 193 [00447] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.04 (d, 2H), 7.77 (s, 1H), 7.02 (dd, 1H), 6.89 (dd, 1H), 6.80-6.70 (m, 2H), 4.08 (s, 2H), 3.90 (s, 3H), 3.42 (s, 2H), 3.08 (m, 1H), 1.20-1.09 (m, 12H). m/z 505.2 (M + H).sup.+ (ES.sup.+); 503.2 (M H).sup. (ES.sup.). 504.58 194 [00448] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.05 (d, 1H), 7.70 (d, 1H), 7.02 (dd, 1H), 6.92 (dd, 1H), 6.80 (s, 1H), 6.72 (dd, 1H), 6.61 (d, 1H), 3.91 (s, 3H), 3.58 (s, 2H), 3.45 (s, 2H), 3.22 (s, 3H), 3.16-3.00 (m, 1H), 1.56 (s, 6H), 1.14 (d, 6H). m/z 519.2 (M + H).sup.+ (ES.sup.+); 517.2 (M H).sup. (ES.sup.). 518.60 195 [00449] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.08 (d, 1H), 7.72 (d, 1H), 7.07-6.98 (m, 1H), 6.94 (d, 1H), 6.80 (s, 1H), 6.76-6.69 (m, 1H), 6.59 (d, 1H), 3.91 (s, 3H), 3.74 (s, 2H), 3.47 (s, 2H), 3.14-2.99 (m, 1H), 1.54 (s, 6H), 1.15 (d, 6H). m/z 505.2 (M + H).sup.+ (ES.sup.+); 503.2 (M H).sup. (ES.sup.). 504.58 196 [00450] 1H NMR (400 MHz, DMSO-d6) 12.19 (s, 1H), 8.12 (d, J = 5.2 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.88 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz, 1H), 6.74-6.72 (m, 1H), 6.65 (s, 1H), 6.49 (s, 1H), 5.55 (br s, 1H), 5.31-5.28 (m, 1H), 3.87 (s, 3H), 3.52 (s, 2H), 2.78- 2.77 (m, 1H), 1.49 (s, 6H), 1.37 (d, J = 6.4 Hz, 6H), 1.05 (d, J = 6.8 Hz, 6H). m/z 533.3 (M + H).sup.+ (ES.sup.+). 532.63 197 [00451] 1H NMR (400 MHz, DMSO-d6 + D2O) 8.12 (d, J = 4.4 Hz, 1H), 7.14 (dd, J1 = 2.8 Hz, J2 = 10.8 Hz, 1H), 6.85-6.80 (m, 2H), 6.71 (s, 1H), 6.41 (s, 1H), 3.98 (s, 3H), 3.85 (s, 3H), 3.40 (s, 2H), 2.88-2.87 (m, 1H), 1.46 (s, 6H), 1.05 (d, J = 6.8 Hz, 6H), 1 NH and 1 OH were missing. m/z 505.1 (M + H).sup.+ (ES.sup.+). 504.57 198 [00452] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.87 (d, 1H), 8.76 (d, 1H), 8.43 (t, 1H), 8.02 (d, 1H), 6.99 (dd, 1H), 6.83 (dd, 1H), 6.77- 6.66 (m, 2H), 3.88 (s, 3H), 3.41 (s, 2H), 3.03-2.89 (m, 1H), 1.56 (s, 6H), 1.06 (dd, 6H). m/z 502.0 (M + H).sup.+ (ES.sup.+); 500.2 (M H).sup. (ES.sup.). 501.57 199 [00453] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.02 (dd, 1H), 7.38 (s, 1H), 7.02 (dd, 1H), 6.92 (dd, 1H), 6.80 (dd, 1H), 6.73 (dd, 1H), 3.90 (s, 3H), 3.43 (s, 2H), 3.10 (m, 1H), 2.54 (s, 3H), 1.91- 1.66 (m, 4H), 1.14 (d, 6H), 0.80 (t, 6H). m/z 549.2 (M + H).sup.+ (ES.sup.+); 547.2 (M H).sup. (ES.sup.). 548.69 200 [00454] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.51 (d, 1H), 8.46 (s, 1H), 7.90-7.80 (m, 2H), 7.46-7.37 (m, 1H), 7.05-6.92 (m, 2H), 6.78-6.69 (m, 1H), 3.42 (s, 2H), 3.25- 3.13 (m, 1H), 3.13- 3.00 (m, 1H), 1.26 (d, 6H), 1.12 (d, 6H). m/z 491.0 (M + H).sup.+ (ES.sup.+); 489.2 (M H).sup. (ES.sup.). 490.54 201 [00455] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.49 (d, 1H), 8.07 (d, 1H), 7.88 (t, 1H), 7.41- 7.35 (m, 1H), 7.06- 6.91 (m, 2H), 6.85 (d, 1H), 6.74 (dd, 1H), 3.42 (s, 2H), 3.19- 3.09 (m, 1H), 3.07 (m, 1H), 1.26 (d, 6H), 1.11 (d, 6H). m/z 491.0 (M + H).sup.+ (ES.sup.+); 489.2 (M H).sup. (ES.sup.). 490.54 202 [00456] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.67- 8.57 (m, 2H), 7.82 (t, 1H), 7.43-7.35 (m, 2H), 6.92 (t, 1H), 3.30 (s, 2H), 3.25- 3.11 (m, 1H), 2.85 (m, 1H), 2.17 (s, 3H), 1.26 (d, 6H), 1.17 (d, 6H). m/z 477.2 (M + H).sup.+ (ES.sup.+); 475.2 (M H).sup. (ES.sup.). 476.54 203 [00457] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.00 (dd, 1H), 7.86 (t, 1H), 7.63 (dd, 1H), 7.01- 6.88 (m, 2H), 6.79- 6.66 (m, 2H), 3.94 (s, 3H), 3.45 (s, 2H), 3.24-3.13 (m, 1H), 3.03 (m, 1H), 1.25 (d, 6H), 1.11 (d, 6H). m/z 521.2 (M + H).sup.+ (ES.sup.+); 519.2 (M H).sup. (ES.sup.). 520.57 204 [00458] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.03 (dd, 1H), 7.85 (t, 1H), 7.09 (d, 1H), 7.02- 6.87 (m, 3H), 6.76 (dd, 1H), 3.89 (s, 3H), 3.44 (s, 2H), 3.18 (m, 1H), 2.90 (t, 2H), 2.78 (t, 2H), 2.10-1.95 (m, 2H), 1.25 (d, 6H). m/z 501.2 (M + H).sup.+ (ES.sup.+); 499.2 (M H).sup. (ES.sup.). 500.56 205 [00459] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 7.99 (dd, 1H), 7.55 (d, 1H), 7.22 (dd, 1H), 7.02 (dd, 1H), 6.95- 6.82 (m, 1H), 6.78 (s, 1H), 6.73 (dd, 1H), 3.88 (s, 3H), 3.44 (s, 2H), 3.18-3.06 (m, 1H), 3.01-2.89 (m, 1H), 1.24 (d, 6H), 1.10 (d, 6H). m/z 491.0 (M + H).sup.+ (ES.sup.+); 489.2 (M H).sup. (ES.sup.). 490.61 206 [00460] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.02 (d, 1H), 7.87 (d, 1H), 7.27-7.13 (m, 2H), 6.98 (dd, 1H), 6.83 (dd, 1H), 6.76-6.64 (m, 2H), 3.89 (s, 3H), 3.46 (s, 2H), 3.20-3.10 (m, 1H), 2.90 (m, 1H), 2.56 (s, 3H), 1.23 (d, 6H), 1.07 (d, 6H). m/z 499.2 (M + H).sup.+ (ES.sup.+); 497.2 (M H).sup. (ES.sup.). 498.61 207 [00461] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.04 (dd, 1H), 7.87 (s, 1H), 7.01 (dd, 1H), 6.87 (dd, 1H), 6.77 (dd, 1H), 6.72 (dd, 1H), 3.99 (t, 2H), 3.90 (s, 3H), 3.43 (s, 2H), 3.02 (m, 1H), 2.36 (s, 3H), 1.82 (m, 2H), 1.10 (d, 6H), 0.88 (t, 3H). m/z 489.2 (M + H).sup.+ (ES.sup.+); 487.2 (M H).sup. (ES.sup.). 488.58 208 [00462] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.05 (dd, 1H), 7.86 (s, 1H), 7.01 (dd, 1H), 6.88 (dd, 1H), 6.81-6.77 (m, 1H), 6.77-6.67 (m, 1H), 3.90 (s, 3H), 3.82 (d, 2H), 3.43 (s, 2H), 3.10-2.94 (m, 1H), 2.36 (s, 3H), 2.12 (dq, 1H), 1.11 (d, 6H), 0.88 (d, 6H). m/z 503.2 (M + H).sup.+ (ES.sup.+); 501.2 (M H).sup. (ES.sup.). 502.61 209 [00463] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.14 (d, 1H), 8.02 (d, 1H), 7.48 (dd, 1H), 7.22 (d, 1H), 6.97 (dd, 1H), 6.83 (dd, 1H), 6.72 (d, 1H), 6.69 (dd, 1H), 5.41 (s, 1H), 5.06 (d, 1H), 3.88 (s, 3H), 3.46 (s, 2H), 3.04-2.90 (m, 1H), 2.59 (s, 3H), 2.13 (dd, 3H), 1.08 (d, 6H). m/z 497.2 (M + H).sup.+ (ES.sup.+); 495.2 (M H).sup. (ES.sup.). 496.60

[1354] Further compounds of the invention may be synthesised by methods analogous to those outlined above.

EXAMPLESBIOLOGICAL STUDIES

NLRP3 and Pyroptosis

[1355] It is well established that the activation of NLRP3 leads to cell pyroptosis and this feature plays an important part in the manifestation of clinical disease (Yan-gang Liu et al., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al., Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59(5), 1691-1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, it is anticipated that inhibitors of NLRP3 will block pyroptosis, as well as the release of pro-inflammatory cytokines (e.g. IL-1) from the cell.

THP-1 Cells: Culture and Preparation

[1356] THP-1 cells (ATCC #TIB-202) were grown in RPMI containing L-glutamine (Gibco #11835) supplemented with 1 mM sodium pyruvate (Sigma #S8636) and penicillin (100 units/ml)/streptomycin (0.1 mg/ml) (Sigma #P4333) in 10% Fetal Bovine Serum (FBS) (Sigma #F0804). The cells were routinely passaged and grown to confluency (10.sup.6 cells/ml). On the day of the experiment, THP-1 cells were harvested and resuspended into RPMI medium (without FBS). The cells were then counted and viability (>90%) checked by Trypan blue (Sigma #T8154). Appropriate dilutions were made to give a concentration of 625,000 cells/ml. To this diluted cell solution was added LPS (Sigma #L4524) to give a 1 g/ml Final Assay Concentration (FAC). 40 l of the final preparation was aliquoted into each well of a 96-well plate. The plate thus prepared was used for compound screening.

THP-1 Cells Pyroptosis Assay

[1357] The following method step-by-step assay was followed for compound screening. [1358] 1. Seed THP-1 cells (25,000 cells/well) containing 1.0 g/ml LPS in 40 l of RPMI medium (without FBS) in 96-well, black walled, clear bottom cell culture plates coated with poly-D-lysine (VWR #734-0317) [1359] 2. Add 5 l compound (8 points half-log dilution, with 10 M top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells [1360] 3. Incubate for 3 hrs at 37 C., 5% CO.sub.2 [1361] 4. Add 5 l nigericin (Sigma #N7143) (FAC 5 M) to all wells [1362] 5. Incubate for 1 hr at 37 C., 5% CO.sub.2 [1363] 6. At the end of the incubation period, spin plates at 300g for 3 mins and remove supernatant [1364] 7. Then add 50 l of resazurin (Sigma #R7017)(FAC 100 M resazurin in RPMI medium without FBS) and incubate plates for a further 1-2 hrs at 37 C. and 5% CO.sub.2 [1365] 8. Plates were read in an Envision reader at Ex 560 nm and Em 590 nm [1366] 9. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)
96-well Plate Map

TABLE-US-00010 1 2 3 4 5 6 7 8 9 10 11 12 A High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low B High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low C High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low D High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low E High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low F High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low G High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low H High Comp 1 Comp 2 Comp 3 Comp 4 Comp 5 Comp 6 Comp 7 Comp 8 Comp 9 Comp 10 Low High MCC950 (10 uM) Compound 8-point half-log dilution Low Drug free control

[1367] The results of the pyroptosis assay are summarised in Table 4 below as THP IC.sub.50.

TABLE-US-00011 TABLE 4 NLRP3 inhibitory activity Example THP No IC.sub.50 1 + 2 ++ 3 +++ 4 +++ 5 +++ 6 + 7 ++ 8 + 9 ++ 10 ++ 11 +++ 12 +++ 13 +++ 14 ++++ 15 ++ 16 ++ 17 ++ 18 + 19 +++ 20 +++ 21 + 22 ++ 23 ++ 24 + 25 ++++ 26 ++++ 27 ++++ 28 ++ 29 ++ 30 ++ 31 ++ 32 +++ 33 ++++ 34 + 35 + 36 ++ 37 ++ 38 +++ 39 + 40 ++++ 41 + 42 + 43 ++ 44 ++ 45 +++ 46 ++ 47 ++ 48 + 49 + 50 + 51 ++ 52 + 53 + 54 ++ 55 ++ 56 + 57 ++ 58 +++ 59 ++ 60 ++ 61 ++ 62 ++ 63 + 64 + 65 ++ 66 ++ 67 +++ 68 ++ 69 ++ 70 ++ 71 ++ 72 ++ 73 ++ 74 + 75 + 76 ++ 77 ++ 78 + 79 +++ 80 ++ 81 ++ 82 ++ 83 ++ 84 +++ 85 ++++ 86 ++ 87 ++++ 88 ++ 89 +++ 90 ++++ 91 ++ 92 ++ 93 +++ 94 +++ 95 + 96 + 97 ++ 98 ++++ 99 ++++ 100 ++++ 101 ++++ 102 + 103 + 104 ++ 105 + 106 ++ 107 ++ 108 ++ 109 + 110 +++ 111 ++ 112 ++ 113 +++ 114 +++ 115 +++ 116 +++ 117 ++++ 118 +++ 119 +++ 120 +++ 121 ++++ 122 ++++ 123 ++++ 124 ++++ 125 ++++ 126 ++++ 127 ++ 128 +++ 129 +++ 130 ++ 131 ++ 132 ++ 133 ++ 134 ++++ 135 ++ 136 +++ 137 + 138 + 139 ++++ 140 ++ 141 +++ 142 +++ 143 +++ 144 ++++ 145 ++++ 146 + 147 ++ 148 ++ 149 ++++ 150 ++++ 151 ++++ 152 ++ 153 ++ 154 ++++ 155 ++ 156 ++++ 157 ++++ 158 ++ 159 ++++ 160 ++ 161 ++ 162 ++ 163 + 164 ++++ 165 ++++ 166 ++++ 167 ++ 168 ++ 169 ++ 170 ++++ 171 ++ 172 ++ 173 ++++ 174 ++++ 175 ++ 176 ++++ 177 ++ 178 +++ 179 ++++ 180 ++ 181 ++++ 182 + 183 +++ 184 +++ 185 ++++ 186 ++++ 187 ++ 188 + 189 ++++ 190 ++ 191 +++ 192 ++ 193 ++ 194 ++ 195 ++ 196 + 197 ++ 198 ++++ 199 ++++ 200 ++++ 201 ++++ 202 ++ 203 ++++ 204 ++ 205 ++++ 206 ++++ 207 +++ 208 ++ 209 ++++ (0.5 M = ++++, 1 M = +++, 5 M = ++, 10 M = +).

PK Protocol

[1368] Pharmacokinetic parameters were determined in male Sprague Dawley rats (Vital River Laboratory Animal Technology Co Ltd, Beijing, China, 7-9 weeks old). Animals were group housed during the study and maintained under a 12 h light/dark cycle.

[1369] For intravenous administration, compounds were formulated as a solution in DMSO:PBS [10:90] in 2 mL/kg dosing volume and administered via tail vein.

[1370] Serial blood samples (about 200 L) were taken from each animal at each of 8 time-points post dose (0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 h). Samples were held on ice for no longer than 30 minutes before centrifugation (5,696 rpm (3,000 g) for 15 minutes) for plasma generation. Plasma was frozen on dry ice prior to bioanalysis. PK parameters were generated from LC-MS/MS data using Phoenix WinNonlin 6.3 software.

TABLE-US-00012 TABLE 5 PK data (intravenous administration) Example Dose AUC T.sub.1/2 V.sub.dss Cl No (mg/kg) (ng .Math. hr/mL) (hr) (L/kg) (mL/min/kg) 54 1 1564.4 4.4 0.95 10.7 67 1 1549.4 16.4 6.52 15.4 69 1 827.1 9.3 6.15 20.2 85 1 925.8 19.8 12.15 29.1 110 1 1257.7 7.2 6.72 13.3

[1371] As is evident from the results presented in Table 4, surprisingly in spite of the structural differences versus the prior art compounds, the compounds of the invention show high levels of NLRP3 inhibitory activity.

[1372] As is evident from the results presented in Table 5, the compounds of the invention show advantageous pharmacokinetic properties, for example half-life T.sub.1/2, area under the curve AUC and/or clearance Cl, compared to the prior art compounds.

[1373] It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention. Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.