Compounds

Abstract

The present invention relates to compounds of formula (I), wherein Q is selected from O or S; R.sup.1 is a 5- or 6-membered heteroaryl group consisting of one or more carbon atoms, and one or more nitrogen and/or oxygen atoms, and substituted with a monovalent, optionally substituted cycloalkyl, cycloalkenyl or heterocyclic group, wherein the 5- or 6-membered heteroaryl group of R.sup.1 may optionally be further substituted; R.sup.2 is an α,α′-substituted cyclic group which 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.sup.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 an optionally substituted C.sub.1-C.sub.4 alkyl group. 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): ##STR00183## or a pharmaceutically acceptable salt or solvate thereof, wherein: Q is selected from O or S; R.sup.1 is a 5- or 6-membered heteroaryl group, wherein the 5- or 6-membered ring structure consists of one or more carbon atoms, and one or more nitrogen and/or oxygen atoms, wherein the 5- or 6-membered heteroaryl group of R.sup.1 is substituted with a monovalent cycloalkyl, cycloalkenyl or heterocyclic group, wherein a ring atom of the monovalent cycloalkyl, cycloalkenyl or heterocyclic group is directly attached to a ring atom of the 5- or 6-membered heteroaryl group of R.sup.1, wherein the monovalent cycloalkyl, cycloalkenyl or heterocyclic group may optionally be substituted, and wherein the 5- or 6-membered heteroaryl group of R.sup.1 may optionally be further substituted; R.sup.2 is a cyclic group substituted at the α and α′ positions, wherein R.sup.2 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(R5).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 an optionally substituted C.sub.1-C.sub.4 alkyl group.

2. The compound or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 1, wherein the 5- or 6-membered heteroaryl group of R.sup.1 is a pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl or oxadiazolyl group.

3. The compound or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 1, wherein the monovalent cycloalkyl, cycloalkenyl or heterocyclic substituent group is a monovalent C.sub.3-C.sub.6 cycloalkyl group which may optionally be substituted.

4. The compound or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 1, wherein R.sup.2 is an aryl or a heteroaryl group, wherein the aryl or the heteroaryl group is substituted at the α and α′ positions, and wherein R.sup.2 may optionally be further substituted.

5. The compound or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 4, wherein R.sup.2 is a fused aryl or a fused heteroaryl group, wherein a first cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group across the α,β positions and a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group across the α′,β′ positions, and wherein R.sup.2 may optionally be further substituted.

6. The compound or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 1, wherein R.sup.2 is a cyclic group substituted at the α-position with a monovalent heterocyclic group or a monovalent aromatic group, wherein a ring atom of the heterocyclic or aromatic group is directly attached to the α-ring atom of the cyclic group, wherein the heterocyclic or aromatic group may optionally be substituted, and wherein the cyclic group is substituted at the α′-position and may optionally be further substituted.

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

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

9. The compound or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 1, wherein the compound is selected from the group consisting of: ##STR00184## ##STR00185## ##STR00186## ##STR00187## ##STR00188## ##STR00189## ##STR00190## ##STR00191## ##STR00192## ##STR00193## ##STR00194## ##STR00195## ##STR00196## ##STR00197## ##STR00198##

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

11. A method of treating, delaying onset of, or reducing risk of 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 or solvate thereof as claimed in claim 1 to the subject, thereby treating, delaying onset of, or reducing risk of the disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

12. The method as claimed in claim 11, 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.

13. The method as claimed in claim 11, 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).

14. The method as claimed in claim 11, wherein the compound is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

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

16. 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 or solvate 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.

17. A prodrug of a compound of formula (I): ##STR00199## or a pharmaceutically acceptable salt or solvate thereof, wherein: Q is selected from O or S; R.sup.1 is a 5- or 6-membered heteroaryl group, wherein the 5- or 6-membered ring structure consists of one or more carbon atoms, and one or more nitrogen and/or oxygen atoms, wherein the 5- or 6-membered heteroaryl group of R.sup.1 is substituted with a monovalent cycloalkyl, cycloalkenyl or heterocyclic group, wherein a ring atom of the monovalent cycloalkyl, cycloalkenyl or heterocyclic group is directly attached to a ring atom of the 5- or 6-membered heteroaryl group of R.sup.1, wherein the monovalent cycloalkyl, cycloalkenyl or heterocyclic group may optionally be substituted, and wherein the 5- or 6-membered heteroaryl group of R.sup.1 may optionally be further substituted; R.sup.2 is a cyclic group substituted at the α and α′ positions, wherein R.sup.2 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 an optionally substituted C.sub.1-C.sub.4 alkyl group.

18. A method of treating, delaying onset of, or reducing risk of a disease, disorder or condition in a subject, the method comprising the step of administering an effective amount of the prodrug as claimed in claim 17 to the subject, thereby treating, delaying onset of, or reducing risk of the disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

Description

EXAMPLES—COMPOUND SYNTHESIS

(1) All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

(2) TABLE-US-00001 Abbreviations 2-MeTHF 2-methyltetrahydrofuran Ac.sub.2O acetic anhydride AcOH acetic acid aq aqueous Boc tert-butyloxycarbonyl br broad Cbz carboxybenzyl CDI 1,1-carbonyl-diimidazole cone concentrated d doublet DABCO 1,4-diazabicyclo[2.2.2]octane DAST diethylaminosulfur trifluoride DCE 1,2-dichloroethane, also called ethylene dichloride DCM dichloromethane DIPEA N,N-diisopropylethylamine, also called Hünig’s base DMA dimethylacetamide DMAP 4-dimethylaminopyridine, also called N,N- dimethylpyridin-4-amine DME dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide eq or equiv equivalent (ES.sup.+) electrospray ionization, positive mode Et ethyl EtOAc ethyl acetate EtOH ethanol h hour(s) HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HPLC high performance liquid chromatography LC liquid chromatography m multiplet m-CPBA 3-chloroperoxybenzoic acid Me methyl MeCN acetonitrile MeOH methanol (M + H).sup.+ protonated molecular ion MHz megahertz min minute(s) MS mass spectrometry Ms mesyl, also called methanesulfonyl MsCl mesyl chloride, also called methanesulfonyl chloride MTBE methyl tert-butyl ether, also called tert-butyl methyl ether m/z mass-to-charge ratio NaHMDS sodium hexamethyldisilazide, also called sodium bis(trimethylsilyl) amide NaO.sup.tBu sodium tert-butoxide NBS 1-bromopyrrolidine-2,5-dione, also called N- bromosuccinimide NCS 1-chloropyrrolidine-2,5-dione, also called N- chlorosuccinimide NMP N -methylpyrrolidine NMR nuclear magnetic resonance (spectroscopy) Pd(OAc).sub.2 palladium acetate Pd(dba).sub.2 bis(dibenzylideneacetone) palladium(o) Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone) dipalladium(o) Pd(dppf)Cl.sub.2 [1,1′-bis(diphenylphosphino)ferrocene] dichloro- palladium(II) PE petroleum ether Ph phenyl PMB p-methoxybenzyl, also called 4-methoxybenzyl prep-HPLC preparative high performance liquid chromatography prep-TLC preparative thin layer chromatography PTSA p-toluenesulfonic acid q quartet RP reversed phase RT room temperature s singlet sat saturated SCX solid supported cation exchange (resin) SEM 2-(trimethylsilyl)ethoxymethyl sept septuplet t triplet T3P propylphosphonic anhydride TBME tert-butyl methyl ether, also called methyl tert-butyl ether TEA triethylamine TFAA 2,2,2-trifluoroacetic acid anhydride TFA 2,2,2-trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMSCl trimethylsilyl chloride wt % weight percent or percent by weight XantPhos ® 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Xphos ® 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl XtalFluor-E ® (diethylamino)difluorosulfonium tetrafluoroborate

Experimental Methods

(3) Analytical Methods

(4) 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: — 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. An Agilent MercuryPlus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, 4 nuclei auto-switchable probe and Mercury plus console. A Bruker Avance III spectrometer at 400 MHz fitted with a BBO 5 mm liquid probe. A Bruker 400 MHz spectrometer using ICON-NMR, under TopSpin program control. A Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe™.

(5) 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 (2.1×50 mm, 2.5 μm).

(6) TABLE-US-00002 Pump flow: 0.6 mL/min UV detection: 215, 238 nm Injection volume: 0.2 μL Run time: 4.0 min Column temperature: 35° C. Mass detection: API-ES +ve and −ive

(7) Pump Program:

(8) TABLE-US-00003 Gradient Time (min) % A % B 0.0 80 20 0.5 80 20 2.0 0 100

(9) 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 2.1×30 mm, 5 μm.

(10) Reversed Phase HPLC Conditions for the LCMS Analytical Methods

(11) Methods 1a and 1b: Waters Xselect CSH C18 XP column (4.6×30 mm, 2.5 μm) at 40° C.; flow rate 2.5-4.5 mL min-1 eluted with a HO-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.

(12) Method 1c: Agilent 1290 series with UV detector and HP 6130 MSD mass detector using Waters XBridge BEH C18 XP column (2.1×50 mm, 2.5 μm) 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.

(13) Reversed Phase HPLC Conditions for the UPLC Analytical Methods

(14) Methods 2a and 2b: Waters BEH C18 (2.1×30 mm, 1.7 μm) at 40° C.; flow rate 0.77 mL min.sup.−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.

(15) Purification Method 1

(16) Automated reversed phase column chromatography was carried out using a Buchi Sepracore®×50 system driven by a C-605 pump module, C-620 Sepracore control package, C-640 UV photometer detection unit and C-660 fraction collector.

(17) Revelis C18 reversed-phase 12 g cartridge

(18) TABLE-US-00004 Carbon loading 18% Surface area 568 m.sup.2/g Pore diameter  65 Angstrom pH (5% slurry) 5.1 Average particle size  40 μm

(19) 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.

(20) Separation Runs:

(21) TABLE-US-00005 Time (min) A: water (%) B: MeOH (%) 0 10 0 5 100 0 30 30 70 30.1 0 100 35 0 100

(22) Detection wavelength: 215, 235, 254 and 280 nm. Before each new run, the cartridge was cleaned using the conditioning method.

(23) Purification Method 2

(24) 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 (100×30 mm; 5 μm).

(25) TABLE-US-00006 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

(26) Pump Program:

(27) TABLE-US-00007 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

(28) Purification Method (Acidic Prep)

(29) Preparative reversed phase HPLC was carried out using a Waters X-Select CSH column C18, 5 μm (19×50 mm), flow rate 28 mL min.sup.−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.

(30) Purification Method 4 (Basic Prep)

(31) Preparative reversed phase HPLC was carried out using a Waters X-Bridge Prep column C18, 5 μm (19×50 mm), flow rate 28 mL min.sup.−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.

(32) Alternatively automated reversed phase HPLC column chromatography purification was carried out using:

(33) (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.

(34) (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.

(35) (iii) a TELEDYNE ISCO CombiFlash Rf+150. Detection wavelength: 220 nm and 254 nm and 215 nm.

(36) (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

(37) ##STR00046##

(38) 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.2—CH.sub.2Cl (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.

(39) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(40) ##STR00047##

(41) 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.2—CH.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.

(42) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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).

(43) LCMS: m/z 259 (M+H).sup.+ (ES.sup.+).

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

(44) ##STR00048##

(45) 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.

(46) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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).

(47) LCMS: m/z 261 (M+H).sup.+ (ES.sup.+).

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

(48) ##STR00049##

(49) 4-Fluoro-2-(2-methoxypyridin-4-yl)-6-(isopropyl)aniline (200 mg, 768 μmol) 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 μmol) in water (1 mL) was added and the mixture was stirred at 0° C. for 45 minutes. Copper(I) bromide (110 mg, 768 μmol) and copper(II) bromide (172 mg, 768 μmol) 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 (2×50 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.

(50) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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).

(51) LCMS: m/z 324 (M+H).sup.+ (ES.sup.+).

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

(52) ##STR00050##

(53) 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 (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

(54) ##STR00051##

(55) 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.

(56) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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).

(57) 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

(58) ##STR00052##

(59) 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.

(60) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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).

(61) LCMS: m/z 302 (M−H).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

(62) ##STR00053##

(63) 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%).

(64) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(65) ##STR00054##

(66) A solution of 5-(benzyloxy)-4-bromo-2,3-dihydro-1H-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 μmol, 0.05 eq) and dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphane (288 mg, 604 μmol, 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%).

(67) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(68) ##STR00055##

(69) 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 μmol, 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 μmol, 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%).

(70) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(71) ##STR00056##

(72) 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%).

(73) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(74) ##STR00057##

(75) 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 μmol, 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 μmol, 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 umol, 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 μmol, 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%).

(76) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(77) ##STR00058##

(78) A solution of tert-butyl 2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetate (172 mg, 507 μmol, 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 μmol, 89%).

(79) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 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

(80) ##STR00059##

(81) 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 μL, 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

(82) ##STR00060##

(83) 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%).

(84) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(85) ##STR00061##

(86) 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%).

(87) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(88) ##STR00062##

(89) 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.

(90) .sup.1H NMR (of 2-(5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid) (300 MHz, CDCl.sub.3) δ 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)acetyl chloride

(91) ##STR00063##

(92) 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 μL, 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

(93) ##STR00064##

(94) 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 μL, 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.

(95) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(96) ##STR00065##

(97) 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.

(98) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(99) ##STR00066##

(100) 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.

(101) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(102) ##STR00067##

(103) 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.

(104) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(105) ##STR00068##

(106) 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.

(107) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(108) ##STR00069##

(109) 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.

(110) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(111) ##STR00070##

(112) 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.

(113) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(114) ##STR00071##

(115) 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.

(116) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(117) ##STR00072##

(118) 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.

(119) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(120) ##STR00073##

(121) 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. PdCl.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.

(122) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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).

(123) LCMS: m/z 288 (M+H).sup.+ (ES.sup.+).

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

(124) ##STR00074##

(125) 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.

(126) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(127) ##STR00075##

(128) 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 μL, 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.

(129) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(130) ##STR00076##

(131) 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.

(132) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(133) ##STR00077##

(134) 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.

(135) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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).

(136) LCMS: m/z 231 (M+H).sup.+ (ES.sup.+).

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

(137) ##STR00078##

(138) 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 (1 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 (2×250 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.

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

(140) LCMS: m/z 294 (M+H).sup.+ (ES.sup.+).

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

(141) ##STR00079##

(142) 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.

(143) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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).

(144) LCMS: m/z 274 (M-tBu+2H).sup.+ (ES.sup.+).

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

(145) ##STR00080##

(146) 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).

(147) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 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

(148) ##STR00081##

(149) 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 μL, 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

(150) ##STR00082##

(151) 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 hours under N.sub.2 atmosphere. Then the reaction mixture was quenched by addition of H.sub.2O (600 mL) and extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine (2×600 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.

(152) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(153) LCMS: m/z 152.2 (M+H).sup.+ (ES.sup.+).

Step B: 4-Fluoro-2-isopropylaniline

(154) ##STR00083##

(155) 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).

(156) 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.

(157) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(158) LCMS: m/z 154.2 (M+H).sup.+ (ES.sup.+).

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

(159) ##STR00084##

(160) 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 (2×250 mL). The combined organic layers were washed with brine (2×400 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.

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

(162) 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

(163) ##STR00085##

(164) 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.

(165) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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

(166) ##STR00086##

(167) 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 (2×150 mL). The combined organic layers were washed with brine (2×200 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.

(168) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(169) LCMS: m/z 256.1 (M+H).sup.+ (ES.sup.+).

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

(170) ##STR00087##

(171) 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 (2×150 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.

(172) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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). 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

(173) ##STR00088##

(174) 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 μmol, 0.05 eq) and Xphos (149 mg, 313.31 μmol, 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 (3×20 mL). The combined organic layers were washed with brine (2×30 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.

(175) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.60 (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).

(176) 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

(177) ##STR00089##

(178) To a mixture of tert-butyl 2-(2-(2-carbamoylpyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetate (130 mg, 222.35 μmol, 1 eq) in DCM (1 mL) was added TFAA (93 mg, 444.70 μmol, 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 (2×2 mL). The combined organic layers were washed with brine (2×2 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.

(179) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(180) LCMS: m/z 355.1 (M+H).sup.+ (ES.sup.+).

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

(181) ##STR00090##

(182) To a solution of tert-butyl 2-(2-(2-cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetate (30 mg, 84.65 μmol, 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 (2×1 mL). The combined organic layers were washed with brine (2×2 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.

(183) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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). 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

(184) ##STR00091##

(185) 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 (2×400 mL). The combined organic layers were washed with water (500 mL), saturated aqueous NaHCO.sub.3 solution (500 mL) and brine (2×500 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.

(186) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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

(187) ##STR00092##

(188) 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.

(189) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(190) LCMS: m/z 134.2 (M+H).sup.+ (ES.sup.+).

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

(191) ##STR00093##

(192) 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 (2×300 mL). The combined organic layers were washed with brine (2×500 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.

(193) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(194) LCMS: m/z 176.2 (M+H).sup.+ (ES.sup.+).

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

(195) ##STR00094##

(196) 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 (2×500 mL). The combined organic layers were washed with brine (2×500 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.

(197) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(198) LCMS: m/z 254.1 (M+H).sup.+ (ES.sup.+).

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

(199) ##STR00095##

(200) 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.

(201) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 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).

(202) 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

(203) ##STR00096##

(204) 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 (3×300 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.

(205) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(206) LCMS: m/z 260.2 (M+H).sup.+ (ES.sup.+).

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

(207) ##STR00097##

(208) 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 (3×300 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.

(209) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(210) LCMS: m/z 235.9 (M+H).sup.+ (ES.sup.+).

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

(211) ##STR00098##

(212) 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. 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 (3×50 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.

(213) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(214) LCMS: m/z 298.9 (M+H).sup.+ (ES.sup.+).

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

(215) ##STR00099##

(216) 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

(217) ##STR00100##

(218) 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 μmol, 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 (3×30 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.

(219) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(220) 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

(221) ##STR00101##

(222) 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.

(223) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 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).

(224) 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

(225) ##STR00102##

(226) 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 (2×30 mL). The combined organic layers were washed with brine (2×50 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.

(227) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(228) 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

(229) ##STR00103##

(230) 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 (3×30 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 μm; 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.

(231) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(232) 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

(233) ##STR00104##

(234) To a mixture of ethyl 2-bromo-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate (430 mg, 807.02 μmol, 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 (3×15 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.

(235) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(236) 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

(237) ##STR00105##

(238) To a mixture of ethyl 2-acetoxy-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetate (150 mg, 385.19 μmol, 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 5˜6 with 1N aqueous HCl solution and then the mixture was extracted with EtOAc (3×15 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.

(239) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(240) 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

(241) ##STR00106##

(242) To a mixture of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)-2-hydroxyacetic acid (95 mg, 297.50 μmol, 1 eq) in DCM (1 mL) was added DMAP (4 mg, 29.75 μmol, 0.1 eq) and Ac.sub.2O (91 mg, 892.50 μmol, 3 eq). The reaction mixture was stirred at 20° C. for 12 hours, and then diluted with water (2 mL) and extracted with DCM (3×2 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.

(243) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(244) LCMS: m/z 362.0 (M+H).sup.+ (ES.sup.+).

Intermediate A10: 2-(4-Fluoro-2,6-diisopropylphenyl)acetic acid

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

(245) ##STR00107##

(246) A solution of 2,6-dibromo-4-fluoroaniline (10 g, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (16.67 g, 2.67 eq), Cs.sub.2CO.sub.3 (36.35 g, 3 eq) and Pd(dppf)Cl.sub.2 (2.72 g, 3.72 mmol, 0.1 eq) in dioxane (100 mL) and H.sub.2O (10 mL) was degassed under reduced pressure. The reaction mixture was heated to 100° C. for 3 hours under nitrogen. Then the reaction mixture was quenched by addition of H.sub.2O (200 mL), diluted with EtOAc (150 mL), and extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine (2×200 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 (8 g, 89% yield, 78.9% purity on LCMS) as a yellow oil.

(247) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.68 (d, 2H), 5.32-531 (m, 2H), 5.08 (d, 2H), 3.84 (s, 2H) and 2.07 (d, 6H).

(248) LCMS: m/z 192.2 (M+H).sup.+ (ES.sup.+).

Step B: 4-Fluoro-2,6-diisopropylaniline

(249) ##STR00108##

(250) To a solution of 4-fluoro-2,6-di(prop-1-en-2-yl)aniline (8 g, 1 eq) in MeOH (150 mL) was added Pd/C (624 mg, 10 wt % loading on activated carbon). The reaction mixture was degassed and purged with H.sub.2 (20 psi). The reaction mixture was stirred at 25° C. for 12 hours under H.sub.2 (20 psi), and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, only eluting with petroleum ether) to give the title compound (4 g, 63% yield, 100% purity on LCMS) as a colourless oil.

(251) 1H NMR (400 MHz, CDCl.sub.3) δ 6.76 (d, 2H), 3.56 (s, 2H), 2.99-2.89 (m, 2H) and 1.26 (d, 12H).

(252) LCMS: m/z 196.2 (M+H).sup.+ (ES.sup.+).

Step C: 2-Bromo-5-fluoro-1,3-diisopropylbenzene

(253) ##STR00109##

(254) To a solution of 4-fluoro-2,6-diisopropylaniline (3.7 g, 18.95 mmol, 1 eq) in MeCN (180 mL) was added CuBr (4.08 g, 1.5 eq). Then tert-butyl nitrite (2.93 g, 1.5 eq) was added dropwise at 0° C. The resulting mixture was stirred at 60° C. for 1.5 hours, and then concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, only eluting with petroleum ether) to give the title compound (2.02 g, 41%) as a white solid.

(255) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.85 (d, 2H), 3.55-3.48 (m, 2H) and 1.24 (d, 12H).

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

(256) ##STR00110##

(257) A mixture of zinc (80 g) in HCl (1 M, 308 mL) was stirred at 25° C. for 30 minutes. Then the mixture was filtered and the filter cake was dried in vacuo. To a mixture of the above 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) at 20° C. under N.sub.2 atmosphere. Then tert-butyl 2-bromoacetate (55 g, 281.97 mmol, 1 eq) was added at 50° C. under N.sub.2 atmosphere. The reaction mixture was stirred at 50° C. for 2 hours. Then the reaction mixture (theory amount: 0.5 M, 550 mL, in THF solution) was cooled and used into the next step without further purification.

Step E: tert-Butyl 2-(4-fluoro-2,6-diisopropylphenyl)acetate

(258) ##STR00111##

(259) A solution of 2-bromo-5-fluoro-1,3-diisopropylbenzene (16 g, 61.74 mmol, 1 eq) in THF (100 mL) was cooled to 0° C. Then Pd.sub.2(dba).sub.3 (2.83 g, 3.09 mmol, 0.05 eq), Xphos (2.94 g, 6.17 mmol, 0.1 eq) and (2-(tert-butoxy)-2-oxoethyl) zinc (II) bromide (0.5 M, 246.95 mL, in THF solution, 2 eq) were added. The reaction mixture was stirred at 70° C. for 12 hours, and then concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether: ethyl acetate, 100:0 to 10:1) to give the title compound (12 g, 59% yield, 90% purity on .sup.1H NMR) as a red oil.

(260) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.83 (d, 2H), 3.66 (s, 2H), 3.21-3.14 (m, 2H), 1.43 (s, 9H) and 1.21 (d, 12H).

Step F: 2-(4-Fluoro-2,6-diisopropylphenyl)acetic acid

(261) ##STR00112##

(262) To a solution of tert-butyl 2-(4-fluoro-2,6-diisopropylphenyl)acetate (12 g, 40.76 mmol, 1 eq) in DCM (120 mL) was added TFA (184.80 g, 39.76 eq). The reaction mixture was stirred at 25° C. for 3 hours. Most of the solvents were evaporated under reduced pressure. The residue was diluted with H.sub.2O (300 mL) and the mixture was adjusted to pH 10 with 2M aqueous NaOH solution. The mixture was washed with EtOAc (3×500 mL) and the organic phases were discarded. Then the aqueous layer was adjusted to pH 3 with 1M aqueous HCl solution and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (2×200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (8 g, 82%) as a yellow solid.

(263) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.24 (br s, 1H), 6.91 (d, 2H), 3.78 (s, 2H), 3.16-3.06 (m, 2H) and 1.18 (d, 12H).

Intermediate P1: 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

(264) ##STR00113##

(265) 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 (2×200 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.

(266) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(267) 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

(268) ##STR00114##

(269) 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 μmol, 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 (2×80 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.

(270) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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

(271) ##STR00115##

(272) 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 (3×20 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.

(273) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.60 (s, 1H), 7.25-719 (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).

(274) LCMS: m/z 321.0 (M+H).sup.+ (ES.sup.+).

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

(275) ##STR00116##

(276) 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 (3×20 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.

(277) .sup.1H NMR (400 MHz, CD.sub.3OD) δ 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).

(278) LCMS: m/z 191.1 (M+H).sup.+ (ES.sup.+).

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

(279) ##STR00117##

(280) 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 (3×20 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.

(281) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 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).

(282) LCMS: m/z 231.2 (M+H).sup.+ (ES.sup.+).

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

(283) ##STR00118##

(284) To a solution of 4-(benzylthio)-1-cyclopropyl-1H-imidazole (100 mg, 434.16 μmol, 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 (2×20 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

(285) ##STR00119##

(286) 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.

(287) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 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).

(288) LCMS: m/z 188.1 (M+H).sup.+ (ES.sup.+).

Intermediate P2: 1-Cyclopropyl-1H-pyrazole-3-sulfonamide

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

(289) ##STR00120##

(290) 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 (3×50 mL). The combined organic layers were washed with brine (2×33 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.

(291) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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

(292) ##STR00121##

(293) 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 (3×500 mL). The combined organic layers were washed with brine (2×250 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.

(294) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(295) LCMS: m/z 124.2 (M+H).sup.+ (ES.sup.+).

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

(296) ##STR00122##

(297) 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 (0 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 (3×250 mL). The combined organic layers were washed with brine (2×150 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.

(298) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.62 (d, 1H), 6.83 (d, 1H), 3.78-372 (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

(299) ##STR00123##

(300) 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 (3×500 mL). The combined organic layers were washed with brine (2×500 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 (3×1). The combined organic layers were washed with brine (2×500 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).

(301) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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), 1.15-113 (m, 2H) and 1.09-1.06 (m, 2H).

(302) LCMS: m/z 428.2 (M+H).sup.+ (ES.sup.+).

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

(303) ##STR00124##

(304) 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). 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, 90% purity on LCMS) as a white solid.

(305) .sup.1H NMR (DMSO-d.sub.6): δ 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 P3: 2-Cyclopropyl-2H-1,2,3-triazole-4-sulfonamide

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

(306) ##STR00125##

(307) 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.

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

(309) LCMS: m/z 192.1 (M+H).sup.+ (ES.sup.+).

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

(310) ##STR00126##

(311) 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.

(312) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 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).

(313) LCMS: m/z 232.1 (M+H).sup.+ (ES.sup.+).

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

(314) ##STR00127##

(315) 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 (2×60 mL). The combined organic layers were washed with brine (3×60 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

(316) ##STR00128##

(317) 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.

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

(319) LCMS: m/z 189.1 (M+H).sup.+ (ES.sup.+).

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

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

(320) ##STR00129##

(321) 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.

(322) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.50 (s, 1H), 7.48 (s, 1H), 3.64-358 (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

(323) ##STR00130##

(324) 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 μmol, 0.05 eq), CuI (98 mg, 512.74 μmol, 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 (3×10 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.

(325) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(326) LCMS: m/z 245.1 (M+H).sup.+ (ES.sup.+).

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

(327) ##STR00131##

(328) 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 (2×40 mL). The combined organic layers were washed with brine (1 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

(329) ##STR00132##

(330) 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.

(331) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 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).

(332) LCMS: m/z 188.1 (M+H).sup.+ (ES.sup.+).

Intermediate P5: 1-Cyclopropyl-5-((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide

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

(333) ##STR00133##

(334) 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. Then the reaction mixture was 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). The resulting mixture was stirred at 70° C. for 2 hours, and then 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 (3×50 mL). The combined organic layers were washed with brine (2×33 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.

(335) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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

(336) ##STR00134##

(337) 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.2O (150 mL). Then 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 (3×500 mL). The combined organic layers were washed with brine (2×250 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.

(338) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(339) LCMS: m/z 124.2 (M+H).sup.+ (ES.sup.+).

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

(340) ##STR00135##

(341) 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 mixture 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 into the reaction mixture. 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 (3×250 mL). The combined organic layers were washed with brine (2×150 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.

(342) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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

(343) ##STR00136##

(344) 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 (3×500 mL). The combined organic layers were washed with brine (2×500 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 (3×1). The combined organic layers were washed with brine (2×500 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).

(345) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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), 1.15-113 (m, 2H) and 1.09-1.06 (m, 2H).

(346) LCMS: m/z 428.2 (M+H).sup.+ (ES.sup.+).

Step E

1-Cyclopropyl-5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

(347) ##STR00137##

(348) A solution of n-BuLi (2.5 M in THF, 1 eq) in THF (8.89 mL) was added dropwise to a stirred solution of 1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (10 g, 22.22 mmol, 1 eq) in THF (250 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 hour. Then N-methyl-N-methylenemethanaminium iodide (8.22 g, 44.44 mmol, 2 eq) was added. The reaction mixture was stirred at −78° C. for 0.5 hour and then warmed to 25° C. for 0.5 hour. The reaction mixture was diluted with saturated aqueous NH.sub.4Cl solution (150 mL) and extracted with EtOAc (3×250 mL). The combined organic layers were washed with brine (2×100 mL), dried over N.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether: ethyl acetate, 10:1 to 0:1) to give the title compound (9 g, 82% yield, 97.9% purity on LCMS) as a yellow oil.

(349) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.03-7.00 (m, 4H), 6.83-6.78 (m, 4H), 6.56 (s, 1H), 4.20 (s, 4H), 3.82-3.76 (m, 1H), 3.71 (s, 6H), 3.57 (s, 2H), 2.19 (s, 6H) and 1.09-0.99 (m, 4H).

(350) LCMS: m/z 485.2 (M+H).sup.+ (ES.sup.+).

Step F: 1-Cyclopropyl-5-((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide

(351) ##STR00138##

(352) To a solution of 1-cyclopropyl-5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (1 g, 2.06 mmol, 1 eq) in DCM (20 mL) was added TFA (15.40 g, 135.06 mmol, 65.45 eq). The reaction mixture was stirred at 25° C. for 12 hours, and then concentrated under reduced pressure to remove TFA. The residue was treated with MeOH (100 mL). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with EtOAc (30 mL) to give the title compound (460 mg, 55% yield, 89% purity on LCMS, TFA salt) as a white solid.

(353) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.51 (s, 2H), 6.85 (s, 1H), 4.58 (s, 2H), 3.92-3.85 (m, 1H), 2.84 (s, 6H) and 1.19-1.09 (m, 4H).

(354) LCMS: m/z 245.2 (M+H).sup.+ (ES.sup.+).

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

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

(355) ##STR00139##

(356) 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 (3×150 mL). The combined organic layers were washed with brine (3×100 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.

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

(358) LCMS: m/z 192.1 (M+H).sup.+ (ES.sup.+).

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

(359) ##STR00140##

(360) 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.

(361) .sup.1H NMR (400 MHz, CD.sub.3OD) δ 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).

(362) LCMS: m/z 232.1 (M+H).sup.+ (ES.sup.+).

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

(363) ##STR00141##

(364) 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 (2×70 mL). The combined organic layers were washed with brine (3×80 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

(365) ##STR00142##

(366) 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.

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

(368) LCMS: m/z 189.1 (M+H).sup.+ (ES.sup.+).

Intermediate P7: 1-Isopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide

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

(369) ##STR00143##

(370) 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 (3×300 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.

(371) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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

(372) ##STR00144##

(373) 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.

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

(375) LCMS: m/z 126.2 (M+H).sup.+ (ES.sup.+).

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

(376) ##STR00145##

(377) 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 (2×700 mL. The combined organic layers were washed with brine (2×700 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.

(378) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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

(379) ##STR00146##

(380) 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 (2×500 mL). The combined organic layers were washed with brine (2×500 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.

(381) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(382) LCMS: m/z 452.2 (M+Na)+(ES.sup.+).

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

(383) ##STR00147##

(384) 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.4Cl solution (10 mL), poured into water (500 mL) and extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with brine (2×500 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.

(385) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 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).

(386) 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

(387) ##STR00148##

(388) 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.4Cl solution (10 mL) slowly, poured into water (800 mL) and extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with brine (3×500 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.

(389) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(390) LCMS: m/z 516.3 (M+H).sup.+ (ES.sup.+).

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

(391) ##STR00149##

(392) 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.

(393) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 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).

(394) LCMS: m/z 276.1 (M+H).sup.+ (ES.sup.+).

SYNTHESIS OF EXAMPLES

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

(395) ##STR00150##

(396) To a solution of 1-cyclopropyl-1H-pyrazole-3-sulfonamide (Intermediate P2) (29 mg, 0.15 mmol, 1.3 eq) in anhydrous dichloromethane (2 mL) was added triethylamine (34 μL, 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-1H-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 μmol, 2%).

(397) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 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).

(398) LCMS: m/z 448 (M+H).sup.+ (ES.sup.+).

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

(399) ##STR00151##

(400) To a suspension of 1-cyclopropyl-1H-pyrazole-3-sulfonamide (Intermediate P2) (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 umol, 2%).

(401) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 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).

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

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

(403) ##STR00152##

(404) 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 μmol, 1 eq), EDC (47 mg, 245.70 μmol, 2 eq) and DMAP (23 mg, 184.28 μmol, 1.5 eq) in DMF (1 mL) was added 1-cyclopropyl-1H-imidazole-4-sulfonamide (Intermediate P1) (23 mg, 122.85 μmol, 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, 150 mm*25 mm*5 μm; mobile phase [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 14%-44%, 10 min) to give the title compound (7.72 mg, 13% yield, 100% purity on LCMS) as a white solid.

(405) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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 (In, 10H).

(406) LCMS: m/z 473.1 (M+H).sup.+ (ES.sup.+).

Example 4

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

(407) ##STR00153##

(408) 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 μmol, 1 eq) in DMF (0.5 mL) was added CDI (40 mg, 247.26 μmol, 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 P2) (40 mg, 214.29 μmol, 1.3 eq) in DMF (0.5 mL) was added NaH (9 mg, 247.26 μmol, 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 μm; 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.

(409) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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), 3.51-342 (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).

(410) LCMS: m/z 473.3 (M+H).sup.+ (ES.sup.+).

Example 5

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

(411) ##STR00154##

(412) 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 μmol, 1 eq) and DMAP (64 mg, 531.33 μmol, 2 eq) in DMF (3.5 mL) was added EDC (101 mg, 531.33 μmol, 2 eq). The mixture was stirred at 25° C. for 10 minutes. Then 2-cyclopropyl-2H-1,2,3-triazole-4-sulfonamide (Intermediate P3) (50 mg, 265.66 μmol, 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.

(413) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(414) LCMS: m/z 454.3 (M+H).sup.+ (ES.sup.+).

Example 6

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

(415) ##STR00155##

(416) To a solution A of 1-cyclopropyl-1H-imidazole-4-sulfonamide (Intermediate P1) (40 mg, 213.65 μmol, 1 eq) in DMF (1 mL) was added NaH (12 mg, 320.48 μmol, 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 μmol, 1 eq) in DMF (1 mL) was added CDI (41 mg, 256.38 μmol, 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.

(417) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(418) LCMS: m/z 443.0 (M+H).sup.+ (ES.sup.+).

Example 7

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

(419) ##STR00156##

(420) To a mixture of 2-cyclopropyl-2H-1,2,3-triazole-4-sulfonamide (Intermediate P3) (22 mg, 119.55 μmol, 1.5 eq) and 2-(2-(2-cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid (Intermediate A7) (23 mg, 79.70 μmol, 1 eq) in DMF (0.5 mL) was added DMAP (10 mg, 87.67 μmol, 1.1 eq) and EDC (30 mg, 159.40 μmol, 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 μm; 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.

(421) .sup.1H NMR (400 MHz, CD.sub.3OD) δ 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).

(422) LCMS: m/z 469.2 (M+H).sup.+ (ES.sup.+).

Example 8

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

(423) ##STR00157##

(424) 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 μmol, 1 eq) in DMF (1 mL) was added EDC (104 mg, 539.96 μmol, 2 eq), DMAP (66 mg, 539.96 μmol, 2 eq) and 2-cyclopropyl-2H-1,2,3-triazole-4-sulfonamide (Intermediate P3) (61 mg, 323.97 μmol, 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.

(425) .sup.1H NMR (400 MHz, CD.sub.3OD) δ 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).

(426) 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

(427) ##STR00158##

(428) 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 μmol, 1 eq) in DCM (5 mL) was added TFAA (27 mg, 128.61 μmol, 2 eq) and TEA (26 mg, 257.23 μmol, 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 (3×10 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 μm; 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.

(429) .sup.1H NMR (400 MHz, CD.sub.3OD) δ 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).

(430) LCMS: m/z 449.0 (M+H).sup.+ (ES.sup.+).

Example 9

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

(431) ##STR00159##

(432) To a mixture of 2-(2-(2-cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)acetic acid (Intermediate A7) (45 mg, 150.85 μmol, 1 eq) in DMF (2 mL) was added EDC (43 mg, 226.27 μmol, 1.5 eq) and DMAP (27 mg, 226.27 μmol, 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 P4) (28 mg, 150.85 μmol, 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.

(433) .sup.1H NMR (400 MHz, CD.sub.3OD) δ 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).

(434) LCMS: m/z 468.2 (M+H).sup.+ (ES.sup.+).

Example 10

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-oxoethylacetate

(435) ##STR00160##

(436) 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 μmol, 1 eq) in DMF (1 mL) was added CDI (10 mg, 62.26 μmol, 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 P4) (11 mg, 62.26 μmol, 1.5 eq) and NaH (2 mg, 62.26 μmol, 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 μm; 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.

(437) .sup.1H NMR (400 MHz, CD.sub.3OD) δ 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).

(438) 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

(439) ##STR00161##

(440) 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 μmol, 1 eq) in MeOH (1 mL) was added K.sub.2CO.sub.3 (2 mg, 17.34 μmol, 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 μm; 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.

(441) .sup.1H NMR (400 MHz, CD.sub.3OD) δ 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).

(442) LCMS: m/z 489.4 (M+H).sup.+ (ES.sup.+).

Example 11

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

(443) ##STR00162##

(444) To the mixture of 2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetic acid (Intermediate A5, Step J) (102 mg, 373.89 μmol, 1 eq), EDC (143 mg, 747.79 μmol, 2 eq) and DMAP (68 mg, 560.84 μmol, 1.5 eq) in DMF (3 mL) was added 1-cyclopropyl-1H-pyrazole-4-sulfonamide (Intermediate P4) (70 mg, 373.89 μmol, 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 μm; 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.

(445) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 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).

(446) LCMS: m/z 443.3 (M+H).sup.+ (ES.sup.+).

Example 12: 2-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)-N-((1-isopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazol-3-yl)sulfonyl)acetamide

(447) ##STR00163##

(448) Et.sub.3N (0.67 mL, 4.80 mmol) and 1-isopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P7) (84 mg, 0.31 mmol) were added to a solution of 2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetyl chloride (60 mg, 0.26 mmol) in DCM (5 mL). The mixture was stirred for 48 hours at room temperature and then concentrated. Purification by column chromatography (SiO.sub.2, 0-6% MeOH in DCM) afforded the title compound.

(449) The product was recrystallized from a heptane/DCM mixture, washed with pentane and dried in vacuo to afford the title compound (48 mg, 39%) as a white solid.

(450) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.91 (s, 1H), 7.09 (s, 1H), 6.96 (s, 1H), 4.96-4.81 (m, 4H), 4.34 (m, 1H), 3.63 (s, 2H), 3.06 (s, 3H), 2.90 (t, 4H), 2.72 (t, 4H), 2.08 (m, 4H), 1.45 (d, 6H).

(451) LCMS: m/z 474 (M+H).sup.+ (ES.sup.+); 472 (M−H).sup.− (ES.sup.−).

Example 13: 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

(452) ##STR00164##

(453) To a solution of 1-isopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P7) (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.

(454) .sup.1H NMR (CD.sub.3OD) δ 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).

(455) LCMS: m/z 536 (M+H).sup.+ (ES.sup.+).

Example 14: N-((1-Cyclopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazol-3-yl)sulfonyl)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetamide

(456) ##STR00165##

(457) Prepared as described for 2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-N-((1-isopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazol-3-yl)sulfonyl)acetamide (Example 12) using 1-cyclopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide (78 mg, 0.28 mmol) and 2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetyl chloride (80 mg, 0.34 mmol) to afford the title compound (71 mg, 53%) as a white solid.

(458) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.82 (s, 1H), 7.09 (s, 1H), 7.00 (s, 1H), 4.93 (s, 4H), 3.67-3.54 (m, 3H), 3.09 (s, 3H), 2.91 (t, 4H), 2.71 (t, 4H), 2.09 (m, 4H), 1.28 (m, 2H), 1.02 (m, 2H).

(459) LCMS: m/z 472 (M+H).sup.+ (ES.sup.+); 470 (M−H).sup.− (ES.sup.−).

Example 15: N-((1-Cyclopropyl-5-(1-(dimethylamino)ethyl)-1H-pyrazol-3-yl)sulfonyl)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetamide

(460) ##STR00166##

(461) Et.sub.3N (0.67 mL, 4.80 mmol) and 1-cyclopropyl-5-(1-(dimethylamino)ethyl)-1H-pyrazole-3-sulfonamide, 2,2,2-trifluoroacetate (130 mg, 0.34 mmol) were added to a solution of 2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetyl chloride (80 mg, 0.34 mmol) in DCM (5 mL). The mixture was stirred for 48 hours at room temperature and then concentrated. Purification by column chromatography (SiO.sub.2, 0-6% MeOH in DCM) afforded the title compound (40 mg, 26%) as a white solid.

(462) .sup.1H NMR (300 MHZ, CDCl.sub.3) δ 7.04 (s, 1H), 6.75 (s, 1H), 4.01 (q, 1H),3.78 (m, 1H), 3.60 (s, 2H), 2.87 (t, 4H), 2.69 (t, 4H), 2.22 (s, 6H), 2.04 (m, 4H), 1.40 (m, 1H), 1.34 (d, 4H), 1.00 (d, 2H).

(463) LCMS: m/z 457 (M+H).sup.+ (ES.sup.+); 455 (M−H).sup.− (ES.sup.−).

Example 16: N-((1-Cyclopropyl-5-((dimethylamino)methyl)-1H-pyrazol-3-yl)sulfonyl)-2-(4-fluoro-2,6-diisopropylphenyl)acetamide

(464) ##STR00167##

(465) To a solution of 1-cyclopropyl-5-((dimethylamino)methyl)-H-pyrazole-3-sulfonamide (Intermediate P5) (70 mg, 286.52 μmol, 1 eq) in DCM (1 mL) and DMF (1 mL) were added EDC (109 mg, 573.03 μmol, 2 eq), DMAP (70 mg, 573.03 μmol, 2 eq) and 2-(4-fluoro-2,6-diisopropylphenyl)acetic acid (Intermediate A10) (68 mg, 286.52 μmol, 1 eq). The reaction mixture was stirred at 25° C. for 2 hours, and then diluted with H.sub.2O (5 mL) and extracted with DCM (3×5 mL). The organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*25 mm*5 μm; mobile phase [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 10%-40%,11.5 min) to give the title compound (25.30 mg, 19% yield, 100% purity on LCMS) as a white solid.

(466) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 6.86 (d, 2H), 6.61 (s, 1H), 3.83-3.79 (m, 1H), 3.71 (s, 2H), 3.59 (s, 2H), 2.93-2.90 (m, 2H), 2.19 (s, 6H) and 1.07-1.03 (m, 16H).

(467) LCMS: m/z 465.3 (M+H).sup.+ (ES.sup.+).

Example 17: N-((1-Cyclopropyl-1H-pyrazol-3-yl)sulfonyl)-2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetamide

(468) ##STR00168##

(469) A solution of 1-cyclopropyl-1H-pyrazole-3-sulfonamide (Intermediate P2) (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. 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 μmol, 23%).

(470) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 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), 348 (s, 2H), 2.93 (t, 2H), 2.79 (t, 2H), 2.08 (q, 2H), 1.13 (dd, 2H), 1.05 (t, 2H).

(471) LC-MS: m/z 453 (M+H).sup.+ (ES.sup.+).

Example 18: N-((1-Cyclopropyl-1H-pyrazol-4-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide, potassium salt

(472) ##STR00169##

(473) 1-Cyclopropyl-H-pyrazole-4-sulfonamide (Intermediate P4) (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.

(474) .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ 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).

(475) LCMS: m/z 473 (M+H).sup.+ (ES.sup.+); 471 (M−H).sup.− (ES.sup.−).

Example 19: N-((1-Cyclopropyl-1H-pyrazol-3-yl)sulfonyl)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetamide

(476) ##STR00170##

(477) Triethylamine (0.67 mL, 4.80 mmol) and 1-cyclopropyl-H-pyrazole-3-sulfonamide (Intermediate P2) (72 mg, 0.38 mmol) were added to a solution of 2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetyl chloride (90 mg, 0.38 mmol) in DCM (5 mL). The reaction mixture was stirred for 48 hours at room temperature and then concentrated. Purification by column chromatography (SiO.sub.2, 0-6% MeOH in DCM) afforded the title compound (15 mg, 10%) as a white solid.

(478) .sup.1H NMR (300 MHz, Methanol-d4) δ 7.78 (s, 1H), 6.93 (s, 1H), 6.75 (s, 1H), 3.77 (m, 1H), 3.58 (s, 2H), 2.82 (t, 4H), 2.68 (t, 4H), 2.01 (m, 4H), 1.20-1.02 (m, 4H).

(479) LCMS: m/z 386 (M+H).sup.+ (ES.sup.+); 384 (M−H).sup.− (ES.sup.−).

Example 20: N-((2-Cyclopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide

(480) ##STR00171##

(481) To a mixture of 2-cyclopropyl-2H-1,2,3-triazole-4-sulfonamide (Intermediate P3) (70 mg, 371.93 μmol, 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 μmol, 1 eq) in DMF (2 mL) were added EDC (107 mg, 557.90 μmol, 1.5 eq) and DMAP (68 mg, 557.90 μmol, 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 μm; 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.

(482) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 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).

(483) LCMS: m/z 474.2 (M+H).sup.+ (ES.sup.+).

Example 21: N-((1-Cyclopropyl-1H-1,2,4-triazol-3-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetamide

(484) ##STR00172##

(485) 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 μmol, 1 eq) in DMF (2 mL) were added 1-cyclopropyl-1H-1,2,4-triazole-3-sulfonamide (Intermediate P6) (70 mg, 371.93 μmol, 1 eq), EDC (107 mg, 557.90 μmol, 1.5 eq) and DMAP (68 mg, 557.90 μmol, 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 μm; 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.

(486) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 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).

(487) LCMS: m/z 474.2 (M+H).sup.+ (ES.sup.+).

Example 22: N-((1-Cyclopropyl-1H-1,2,4-triazol-3-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetamide

(488) ##STR00173##

(489) To the solution of 2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetic acid (Intermediate A5, Step J) (102 mg, 371.93 μmol, 1 eq), EDC (143 mg, 743.86 μmol, 2 eq) and DMAP (68 mg, 557.90 μmol, 1.5 eq) in DMF (1 mL) was added 1-cyclopropyl-1H-1,2,4-triazole-3-sulfonamide (Intermediate P6) (70 mg, 371.93 μmol, 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 μm; 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.

(490) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 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).

(491) LCMS: m/z 444.3 (M+H).sup.+ (ES.sup.+).

Example 23: N-((1-Cyclopropyl-H-pyrazol-4-yl)sulfonyl)-2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetamide

(492) ##STR00174##

(493) To a mixture of 1-cyclopropyl-1H-pyrazole-4-sulfonamide (Intermediate P4) (50 mg, 267.07 μmol, 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 μmol, 1 eq) in DMF (3 mL) were added EDC (102 mg, 534.13 μmol, 2 eq) and DMAP (65 mg, 534.13 μmol, 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 μm; 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.

(494) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 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).

(495) LCMS: m/z 453.3 (M+H).sup.+ (ES.sup.+).

Example 24: N-((1-Cyclopropyl-1H-pyrazol-4-yl)sulfonyl)-2-(4-fluoro-2,6-diisopropylphenyl)acetamide

(496) ##STR00175##

(497) To a mixture of 1-cyclopropyl-1H-pyrazole-4-sulfonamide (Intermediate P4) (50 mg, 267.07 μmol, 1 eq) and 2-(4-fluoro-2,6-diisopropylphenyl)acetic acid (Intermediate 5 A10) (64 mg, 267.07 μmol, 1 eq) in DMF (1 mL) were added EDC (102 mg, 534.13 μmol, 2 eq) and DMAP (65 mg, 534.13 μmol, 2 eq) in one portion. Then the reaction mixture was stirred at 25° C. for 1 hour. The mixture 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 μm; mobile phase [A: water (10 mM NH.sub.4HCO.sub.3), B: MeCN]; B %: 20%-50%, 10 min) to give the title compound (27.19 mg, 53% yield, 99.2% purity on LCMS) as a white solid.

(498) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.41 (s, 1H), 7.76 (s, 1H), 6.86 (d, 2H), 3.83-3.79 (m, 1H), 3.67 (s, 2H), 2.91-2.87 (m, 2H) and 1.04-0.95 (m, 16H).

(499) LCMS: m/z 408.3 (M+H).sup.+ (ES.sup.+).

Example 25: N-((1-Cyclopropyl-H-1,2,4-triazol-3-yl)sulfonyl)-2-(4-fluoro-2,6-diisopropylphenyl)acetamide

(500) ##STR00176##

(501) To a solution of 2-(4-fluoro-2,6-diisopropylphenyl)acetic acid (Intermediate A10) (89 mg, 371.93 μmol, 1 eq) in DMF (1 mL) were added EDC (143 mg, 743.86 μmol, 2 eq), DMAP (68 mg, 557.90 μmol, 1.5 eq) and 1-cyclopropyl-H-1,2,4-triazole-3-sulfonamide (Intermediate P6) (70 mg, 371.93 μmol, 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 μm; mobile phase [A: water (10 mM NH.sub.4HCO.sub.3), B: MeCN]; B %: 22%-48%, 8 min) to give the title compound (33.57 mg, 22% yield, 100% purity on LCMS) as a white solid.

(502) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.06 (s, 1H), 6.86 (d, 2H), 3.87 (s, 2H), 3.68-3.64 (m, 1H), 3.01-2.94 (m, 2H), 1.26-1.23 (m, 4H) and 1.19 (d, 12H).

(503) LCMS: m/z 409.1 (M+H).sup.+ (ES.sup.+).

Example 26: N-((2-Cyclopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-2-(4-fluoro-2,6-diisopropylphenyl)acetamide

(504) ##STR00177##

(505) To a solution of 2-cyclopropyl-2H-1,2,3-triazole-4-sulfonamide (Intermediate P3) (50 mg, 265.66 μmol, 1 eq) in DMF (2 mL) were added EDC (102 mg, 531.33 μmol, 2 eq), DMAP (65 mg, 531.33 μmol, 2 eq) and 2-(4-fluoro-2,6-diisopropylphenyl)acetic acid (Intermediate A10) (63 mg, 265.66 μmol, 1 eq). The reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was purified by reversed phase flash chromatography (0.1% TFA in water-MeCN) and then purified further by prep-HPLC (column: Phenomenex Synergi C18, 150 mm*25 mm*10 μm; mobile phase [A: water (0.1% TFA), B: MeCN]; B %: 45%-69%,10 min) to give the title compound (19 mg, 17% yield, 99% purity on LCMS) as a white solid.

(506) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.77 (br s, 1H), 8.28 (s, 1H), 6.88 (d, 2H), 4.30-4.26 (m, 1H), 3.78 (s, 2H), 2.91-2.85 (m, 2H), 1.21-1.17 (m, 4H) and 1.03 (d, 12H).

(507) LCMS: m/z 409.3 (M+H).sup.+ (ES.sup.+).

Example 27: N-((2-Cyclopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetamide

(508) ##STR00178##

(509) To a solution of 2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetic acid (Intermediate A5, Step J) (102 mg, 371.93 μmol, 1 eq) in DMF (1 mL) were added EDC (143 mg, 743.86 μmol, 2 eq), DMAP (68 mg, 557.90 μmol, 1.5 eq) and 2-cyclopropyl-2H-1,2,3-triazole-4-sulfonamide (Intermediate P3) (70 mg, 371.93 μmol, 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 μm; 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.

(510) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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).

(511) LCMS: m/z 444.1 (M+H).sup.+ (ES.sup.+).

Example 28: N-((1-Cyclopropyl-1H-imidazol-4-yl)sulfonyl)-2-(4-fluoro-2,6-diisopropylphenyl)acetamide

(512) ##STR00179##

(513) To a mixture A of 1-cyclopropyl-1H-imidazole-4-sulfonamide (Intermediate P1) (35 mg, 186.95 μmol, 1 eq) in DMF (1 mL) at 0° C. was added NaH (1 mg, 280.42 μmol, 60 wt % in mineral oil, 1.5 eq) in one portion. Then the mixture A was stirred at 0° C. for 0.5 hour. To a mixture B of 2-(4-fluoro-2,6-diisopropylphenyl)acetic acid (Intermediate A10) (49 mg, 205.64 μmol, 1.1 eq) in DMF (1 mL) at 0° C. was added CDI (36 mg, 224.34 μmol, 1.2 eq) in one portion. Then the mixture B was stirred at 0° C. for 0.5 hour. Then the mixture A was added dropwise to the mixture B, and the resulting mixture was warmed to 25° C. and stirred for 12 hours. The reaction mixture was quenched with water (1 mL). The mixture was directly purified by prep-HPLC (column: Phenomenex Synergi C18, 150 mm*25 mm*10 μm; mobile phase [A: water (0.1% TFA), B: MeCN]; B %: 40%-70%,10 min), and then further purified by prep-HPLC (column: Xtimate C18, 150 mm*25 mm*5 μm; mobile phase [A: water (0.05% ammonium hydroxide v/v), B: MeCN]; B %: 3%-33%, 10 min) to give the title compound (3.23 mg, 4% yield, 100% purity on LCMS) as a white solid.

(514) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.67 (s, 1H), 7.40 (s, 1H), 6.83 (d, 2H), 3.76 (s, 2H), 3.37-3.34 (m, 1H), 2.99-2.93 (m, 2H), 1.12-1.07 (m, 14H) and 0.98-0.95 (m, 2H).

(515) LCMS: m/z 408.2 (M+H).sup.+ (ES.sup.+).

Example 29: 2-(4-Fluoro-2,6-diisopropylphenyl)-N-((1-isopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazol-3-yl)sulfonyl)acetamide

(516) ##STR00180##

(517) To a mixture of 1-isopropyl-5-(3-methoxyoxetan-3-yl)-1H-pyrazole-3-sulfonamide (Intermediate P7) (69 mg, 251.79 μmol, 1 eq) and 2-(4-fluoro-2,6-diisopropylphenyl)acetic acid (Intermediate A10) (60 mg, 251.79 μmol, 1 eq) in DMF (2 mL) were added EDC (97 mg, 503.57 μmol, 2 eq) and DMAP (62 mg, 503.57 μmol, 2 eq) in one portion at 16° C. The reaction mixture was stirred at 16° C. for 1 hour, and then poured into saturated aqueous citric acid solution (10 mL) and extracted with DCM (2×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (Column: Waters Xbridge C18, 150 mm*25 mm*5 μm; mobile phase [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 16%-36%, 10 min) to give the title compound (34 mg, 27% yield, 100% purity on LCMS) as a white solid.

(518) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 6.93 (s, 1H), 6.85 (d, 2H), 4.81-4.77 (m, 4H), 4.26-4.19 (m, 1H), 3.69 (s, 2H), 2.97-2.93 (m, 5H), 1.34 (d, 6H) and 1.04 (d, 12H).

(519) LCMS: m/z 496.2 (M+H).sup.+ (ES.sup.+).

Example 30: 2-(5-(2-Cyanopyridin-4-yl)-2,3-dihydro-H-inden-4-yl)-N-((1-cyclopropyl-1H-pyrazol-4-yl)sulfonyl)acetamide

(520) ##STR00181##

(521) To a suspension of 1-cyclopropyl-1H-pyrazole-4-sulfonamide (Intermediate P4) (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 μmol, 2%).

(522) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 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).

(523) LC-MS: m/z 448 (M+H).sup.+ (ES.sup.+).

Example 31: 2-(2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl)-N-((1-cyclopropyl-1H-imidazol-4-yl)sulfonyl)acetamide

(524) ##STR00182##

(525) A solution (A) of 1-cyclopropyl-H-imidazole-4-sulfonamide (Intermediate P1) (7 mg, 36.20 μmol, 1.2 eq) and NaH (1 mg, 36.20 μmol, 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 μmol, 1 eq) and TEA (6 mg, 60.34 μmol, 2 eq) in THF (0.2 mL) was added isobutyl carbonochloridate (5 mg, 37.71 μmol, 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 μm; 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.

(526) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 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), 3.43-341 (m, 1H), 2.96-2.94 (m, 1H) and 1.11-1.01 (m, 10H).

(527) LCMS: m/z 468.3 (M+H).sup.+ (ES.sup.+).

(528) Further compounds of the invention may be synthesised by methods analogous to those outlined above.

Examples—Biological Studies

(529) NLRP3 and Pyroptosis

(530) 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-1p) from the cell.

(531) THP-1 Cells: Culture and Preparation

(532) 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 μg/ml Final Assay Concentration (FAC). 40 μl of the final preparation was aliquoted into each well of a 96-well plate. The plate thus prepared was used for compound screening.

(533) THP-1 Cells Pyroptosis Assay

(534) The following method step-by-step assay was followed for compound screening. 1. Seed THP-1 cells (25,000 cells/well) containing 1.0 μg/ml LPS in 40 μl of RPMI medium (without FBS) in 96-well, black walled, clear bottom cell culture plates coated with poly-D-lysine (VWR #734-0317) 2. Add 5p compound (8 points half-log dilution, with 100M top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells 3. Incubate for 3 hrs at 37° C., 5% CO.sub.2 4. Add 5 μl nigericin (Sigma #N7143) (FAC 5 μM) to all wells 5. Incubate for 1 hr at 37° C., 5% CO.sub.2 6. At the end of the incubation period, spin plates at 300×g for 3 mins and remove supernatant 7. Then add 50 μl of resazurin (Sigma #R7017) (FAC 100 μM resazurin in RPMI medium without FBS) and incubate plates for a further 1-2 hrs at 37° C. and 5% CO.sub.2 8. Plates were read in an Envision reader at Ex 560 nm and Em 590 nm 9. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

(535) 96-well Plate Map

(536) TABLE-US-00008 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

(537) The results of the pyroptosis assay are summarised in Table 1 below as THP IC.sub.50.

(538) TABLE-US-00009 TABLE 1 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 + (≤1 μM = ‘+++’, ≤5 μM = ‘++’, ≤10 μM = ‘+’).

(539) PK Protocol

(540) 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.

(541) 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.

(542) Serial blood samples (about 200 μL) 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.

(543) TABLE-US-00010 TABLE 2 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) 11 1 1564.4  4.4 0.95 10.7 18 1 1549.4 16.4 6.52 15.4 21 1  827.1  9.3 6.15 20.2 24 1 1274.1  2.6 1.94 13.1

(544) As is evident from the results presented in Table 1, surprisingly in spite of the structural differences versus the prior art compounds, the compounds of the invention show high levels of NLRP3 inhibitory activity.

(545) As is evident from the results presented in Table 2, 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.

(546) 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.