1. Patent Search
  2. Details

NOVEL COMPOUNDS

20200399243 ยท 2020-12-24

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention relates to compounds of formula (1): wherein Q is selected from O or S; R.sup.1 is a 5-membered nitrogen-containing heteroaryl group substituted with R.sup.6 and optionally further substituted; R.sup.2 is an alpha, alpha-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; R.sup.5 is independently an optionally substituted C.sub.1-C.sub.4 alkyl group; and R.sup.6 is any group comprising a nitrogen atom. 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 NLRP.sub.3.

    ##STR00001##

    Claims

    1. A compound of formula (I): ##STR00137## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Q is selected from O or S; R.sup.1 is a 5-membered heteroaryl group, wherein the 5-membered ring structure consists of one or more carbon atoms, one or more nitrogen atoms and optionally one or more oxygen atoms, wherein R.sup.1 is substituted with R.sup.6 and R.sup.1 may optionally be further substituted; R.sup.2 is a cyclic group substituted at the and 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; R.sup.5 is independently an optionally substituted C.sub.1-C.sub.4 alkyl group; and R.sup.6 is any group comprising a nitrogen atom.

    2. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is a monocyclic 5-membered heteroaryl group comprising one, two or three ring nitrogen atoms.

    3. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is a pyrrolyl, imidazolyl or pyrazolyl group.

    4. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.6 is a C.sub.1-C.sub.5 alkyl, C.sub.2C alkenyl or C.sub.2C alkynyl group substituted with one or two substituents independently selected from CN; NO.sub.2; N.sub.3; NH.sub.2; NHR.sup.; N(R.sup.).sub.2; NHCHO; NR.sup.CHO; NHCOR.sup.; NR.sup.COR.sup.; CONH.sub.2; CONHR.sup.; or CON(R.sup.).sub.2; wherein the C.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.5 alkenyl or C.sub.2-C.sub.5 alkynyl group may optionally be further substituted with one or two substituents independently selected from halo; OH; OR.sup.; or oxo (O); and wherein each R.sup. is independently selected from a C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl or C.sub.2-C.sub.4 alkynyl group, and wherein any R.sup. may optionally be substituted with one or more halo; OH; NH.sub.2; CN; NO.sub.2; N.sub.3; or oxo (O).

    5. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.1 is further substituted with one or two substituents independently selected from halo; R.sup.; OH; OR.sup.; R.sup.-halo; R.sup.R.sup.; R.sup.OH; R.sup.OR.sup.; CHO; COR.sup.; COOR.sup.; OCOR.sup.; R.sup.CHO; R.sup.COR.sup.; R.sup.COOR.sup.; R.sup.OCOR.sup.; OR.sup.OH; or OR.sup.OR.sup.; wherein each R.sup. is independently selected from an alkylene, alkenylene or alkynylene group, wherein the alkylene, alkenylene or alkynylene group contains from 1 to 6 atoms in its backbone, wherein one or more carbon atoms in the backbone of the alkylene, alkenylene or alkynylene group may optionally be replaced by one or two heteroatoms N or O, and wherein the alkylene, alkenylene or alkynylene group may optionally be substituted with one or more halo and/or R.sup. groups; and wherein each R.sup. is independently selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl or C.sub.2-C.sub.6 alkynyl group, and wherein any R.sup. may optionally be substituted with one or more halo, OH, NH.sub.2, CN, NO.sub.2, N.sub.3, SH, SO.sub.2H, SO.sub.2NH.sub.2, or oxo (O).

    6. The compound or a pharmaceutically acceptable salt, solvate or prodrug 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 and positions, and wherein R.sup.2 may optionally be further substituted.

    7. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 6, 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 , positions and a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring is fused to the aryl or heteroaryl group across the , positions, and wherein R.sup.2 may optionally be further substituted.

    8. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein R.sup.2 is a cyclic group substituted at the -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 -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 -position and may optionally be further substituted.

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

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

    11. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the compound is selected from the group consisting of: ##STR00138## ##STR00139## ##STR00140## ##STR00141## ##STR00142## ##STR00143## ##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151## ##STR00152## ##STR00153## ##STR00154## ##STR00155## ##STR00156## ##STR00157## ##STR00158## ##STR00159## ##STR00160##

    12. (canceled)

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

    14. (canceled)

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

    16. The method as claimed in claim 15, 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.

    17. The method as claimed in claim 15, 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).

    18. (canceled)

    19. The method as claimed in claim 15, wherein the compound is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

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

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

    Description

    EXAMPLESCOMPOUND SYNTHESIS

    [0346] All solvents, reagents and compounds were purchased and used without further purification unless stated otherwise.

    Abbreviations

    [0347] 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
    conc 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 Hnig's base
    DMA dimethylacetamide
    DMAP 4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine
    DME dimethoxyethane

    DMF N,N-dimethylformamide

    [0348] DMSO dimethyl sulfoxide
    EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
    eq or equiv equivalent
    (ES+) 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

    [0349] NMR nuclear magnetic resonance (spectroscopy)
    Pd(OAc).sub.2 palladium acetate
    Pd(dba).sub.2 bis(dibenzylideneacetone) palladium(0)
    Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone) dipalladium(0)
    Pd(dppf)Cl.sub.2 [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(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

    Analytical Methods

    [0350] 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: [0351] 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. [0352] An Agilent MercuryPlus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, 4 nuclei auto-switchable probe and Mercury plus console. [0353] A Bruker Avance III spectrometer at 400 MHz fitted with a BBO 5 mm liquid probe. [0354] A Bruker 400 MHz spectrometer using ICON-NMR, under TopSpin program control. [0355] A Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe.

    [0356] 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 (mM); water/MeOH/acetonitrile (900:60:40); mobile phase B: ammonium acetate (mM); water/MeOH/acetonitrile (100:540:360); column, Waters XBridge BEH C18 XP (2.150 mm, 2.5 m).

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

    [0357] Pump Program:

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

    [0358] Alternatively LC-MS were recorded using SHIMADZU LCMS-2020, Agilent 1200 LC/G1956A MSD and Agilent 1200G6110A, or Agilent 1200 LC & Agilent 6110 MSD. Mobile Phase: A: 0.025% NH.sub.3.H.sub.2O in water (v/v); B: Acetonitrile. Column: Kinetex EVO C18 2.130 mm, 5 m.

    Reversed Phase HPLC Conditions for the LCMS Analytical Methods

    [0359] Methods 1a and 1b: Waters Xselect CSH C18 XP column (4.630 mm, 2.5 m) at 40 C.; flow rate 2.5-4.5 mL min-1 eluted with a H.sub.2O-MeCN gradient containing either 0.1% v/v formic acid (Method 1a) or 10 mM NH.sub.4HCO.sub.3 in water (Method 1b) over 4 min employing UV detection at 254 nm.

    [0360] Method 1c: Agilent 1290 series with UV detector and HP 6130 MSD mass detector using Waters XBridge BEH C18 XP column (2.150 mm, 2.5 m) at 35 C.; flow rate 0.6 mL/min; mobile phase A: ammonium acetate (10 mM); water/MeOH/acetonitrile (900:60:40); mobile phase B: ammonium acetate (10 mM); water/MeOH/acetonitrile (100:540:360); over 4 min employing UV detection at 215 and 238 nm.

    Reversed Phase HPLC Conditions for the UPLC Analytical Methods

    [0361] Methods 2a and 2b: Waters BEH C18 (2.130 mm, 1.7 m) at 40 C.; flow rate 0.77 mL min-1 eluted with a H.sub.2O-MeCN gradient containing either 0.1% v/v formic acid (Method 2a) or 10 mM NH.sub.4HCO.sub.3 in water (Method 2b) over 3 min employing UV detection at 254 nm.

    Purification Method 1

    [0362] Automated reversed phase column chromatography was carried out using a Buchi Sepracoreo X50 system driven by a C-605 pump module, C-620 Sepracore control package, C-640 UV photometer detection unit and C-660 fraction collector.

    [0363] Revelis C18 reversed-phase 12 g cartridge [0364] Carbon loading 18%

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

    [0365] 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.

    Separation Runs:

    [0366]

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

    [0367] Detection wavelength: 215, 235, 254 and 280 nm. Before each new run, the cartridge was cleaned using the conditioning method.

    Purification Method 2

    [0368] Preparative column chromatography was carried out using a Waters prep system driven by a 2767 Sample Manager, SFO System Fluidics Organizer, 515 HPLC Pumps, 2545 Binary Gradient Module, 2998 Photodiode Array Detector, SQD Detector 2 with ESI mass. Mobile phase ACD: acetonitrile; mobile phase A: ammonium acetate (10 mM); mobile phase B: acetonitrile; column, XSelect CSH Prep C18 OBD (10030 mm; 5 m).

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

    Pump Program:

    [0369]

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

    Purification Method (Acidic Prep)

    [0370] Preparative reversed phase HPLC was carried out using a Waters X-Select CSH column C18, 5 m (1950 mm), flow rate 28 mL min-1 eluting with a H.sub.2O-MeCN gradient containing 0.1% v/v formic acid over 6.5 min using UV detection at 254 nm. Gradient information: 0.0-0.2 min, 20% MeCN; 0.2-5.5 min, ramped from 20% MeCN to 40% MeCN; 5.5-5.6 min, ramped from 40% MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

    Purification Method 4 (Basic Prep)

    [0371] Preparative reversed phase HPLC was carried out using a Waters X-Bridge Prep column C18, 5 m (1950 mm), flow rate 28 mL min-1 eluting with a 10 mM NH.sub.4HCO.sub.3-MeCN gradient over 6.5 min using UV detection at 254 nm. Gradient information: 0.0-0.2 min, 10% MeCN; 0.2-5.5 min, ramped from 10% MeCN to 40% MeCN; 5.5-5.6 min, ramped from 40% MeCN to 95% MeCN; 5.6-6.5 min, held at 95% MeCN.

    [0372] Alternatively automated reversed phase HPLC column chromatography purification was carried out using:

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

    Synthesis of Intermediates

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

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

    [0373] ##STR00057##

    [0374] 2,6-Dibromo-4-fluoroaniline (10.0 g, 37.2 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (6.87 g, 40.9 mmol) and potassium carbonate (15.4 g, 112 mmol) were dissolved in dioxane (8 mL) and water (4 mL) and degassed four times under argon atmosphere. Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (1.52 g, 1.86 mmol) was added and the mixture was refluxed for 48 hours. Water (20 mL) and ethyl acetate (40 mL) were added and the layers were separated. The aqueous layer was extracted with ethyl acetate (30 mL). The combined organic layers were dried over sodium sulfate, evaporated to dryness and subjected to column chromatography (SiO.sub.2, heptanes with 15% ethyl acetate) to yield the title compound (3.5 g, 41%) as a light brown oil.

    [0375] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.10 (dd, 1H), 6.76 (dd, 1H), 5.36 (bs, 1H), 5.08 (bs, 1H), 4.05 (bs, 2H), 2.05 (s, 3H).

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

    [0376] ##STR00058##

    [0377] 2-Bromo-4-fluoro-6-(prop-1-en-2-yl)aniline (8.56 g, 37.2 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (10.5 g, 44.6 mmol) were dissolved in dioxane (10 mL) under N.sub.2 atmosphere. Potassium carbonate (15.4 g, 112 mmol) in water (10 mL) was added. Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (1.52 g, 1.86 mmol) was added and the mixture was stirred overnight at reflux. The dioxane was largely removed by rotary evaporation. Ethyl acetate (100 mL) was added and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to dryness to yield the title compound (8.0 g, 83%) as a brown oil.

    [0378] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.20 (d, 1H), 7.00 (m, 2H), 6.82 (s, 1H), 6.72 (d, 1H), 5.34 (bs, 1H), 5.09 (bs, 1H), 3.98 (s, 3H), 3.80 (bs, 2H), 2.05 (s, 3H).

    [0379] LCMS: m/z 259 (M+H).sup.+ (ES.sup.+).

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

    [0380] ##STR00059##

    [0381] 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.

    [0382] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.21 (d, 1H), 6.98 (dd, 1H), 6.92 (dd, 1H), 6.82 (s, 1H), 6.70 (dd, 1H), 3.98 (s, 3H), 3.61 (bs, 2H),2.91 (m, 1H), 1.25 (d, 6H).

    [0383] LCMS: m/z 261 (M+H).sup.+ (ES.sup.+).

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

    [0384] ##STR00060##

    [0385] 4-Fluoro-2-(2-methoxypyridin-4-yl)-6-(isopropyl)aniline (200 mg, 768 mol) in acetonitrile (12 mL) at 0 C. was treated with concentrated HBr (1.3 g) in water (1 mL). Sodium nitrite (58.3 mg, 845 mol) in water (1 mL) was added and the mixture was stirred at 0 C. for 45 minutes. Copper(I) bromide (110 mg, 768 mol) and copper(II) bromide (172 mg, 768 mol) were added and the mixture was allowed to reach room temperature over 2 hours. The mixture was poured into saturated sodium carbonate solution (so mL. The mixture was extracted with DCM (250 mL. The combined organic layers were dried over sodium sulfate and evaporated to dryness in vacuo to yield the title compound (160 mg, 64%) as a brown oil.

    [0386] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.20 (d, 1H), 7.02 (dd, 1H), 6.85 (d, 1H), 6.82 (dd, 1H), 6.73 (s, 1H), 3.98 (s, 3H), 3.42 (m, 1H), 1.24 (d, 6H).

    [0387] LCMS: m/z 324 (M+H).sup.+ (ES.sup.+).

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

    [0388] ##STR00061##

    [0389] To a mixture of Zn (55 g, 841.11 mmol, 2.98 eq) in THF (550 mL) was added TMSCl (3.06 g, 28.20 mmol, 0.1 eq) and 1,2-dibromoethane (5.30 g, 28.20 mmol, 0.1 eq) under N.sub.2 atmosphere. The mixture was refluxed for 1 hour. After cooling to 40 C., tert-butyl 2-bromoacetate (55 g, 281.97 mmol, 1 eq) was added and the mixture was refluxed for 2 hours. The mixture was cooled, decanted and the supernatant was used into the next step without further purification (crude).

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

    [0390] ##STR00062##

    [0391] 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.

    [0392] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.19 (d, 1H), 7.03 (dd, 1H), 6.82 (d, 1H), 6.78 (dd, 1H), 6.68 (s, 1H), 3.98 (s, 3H), 3.42 (s, 2H), 3.02 (m, 1H), 1.41 (s, 9H), 1.23 (d, 6H).

    [0393] 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

    [0394] ##STR00063##

    [0395] 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.

    [0396] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.19 (d, 1H), 7.03 (dd, 1H), 6.81 (d, 1H), 6.78 (dd, 1H), 6.68 (s, 1H), 3.98 (s, 3H), 3.59 (s, 2H), 3.02 (m, 1H), 1.23 (d, 6H).

    [0397] LCMS: m/z 302 (MH).sup. (ES.sup.).

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

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

    [0398] ##STR00064##

    [0399] 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%).

    [0400] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.52-7.46 (m, 2H), 7.42-7.29 (m, 3H), 7.03 (d, 1H), 6.72 (d, 1H), 5.13 (s, 2H), 2.96 (t, 4H), 2.10 (p, 2H).

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

    [0401] ##STR00065##

    [0402] 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 mol, 0.05 eq) and dicyclohexyl(2,4,6-triisopropyl-[1,1-biphenyl]-2-yl)phosphane (288 mg, 604 mol, 0.1 eq). The reaction mixture was stirred for 30 minutes at room temperature. After that, (2-(tert-butoxy)-2-oxoethyl) zinc (II) bromide (Intermediate A1, Step E) in THF (0.55 molar, 22 mL, 12.1 mmol, 2 eq) was added and the reaction mixture was heated in a sand bath at 70 C. After stirring for 1 hour, the reaction mixture was cooled to room temperature and then diluted with diethyl ether. The reaction mixture was washed twice with saturated ammonium chloride, once with brine, dried over sodium sulfate, filtered and then concentrated in vacuo. The crude product was submitted to normal phase flash chromatography using heptane and ethyl acetate as eluent to afford the title compound (1.82 g, 5.38 mmol, 89%).

    [0403] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.44 (d, 2H), 7.40-7.29 (m, 3H), 7.05 (d, 1H), 6.72 (d, 1H), 5.06 (s, 2H), 3.62 (s, 2H), 2.87 (t, 4H), 2.08 (p, 2H), 1.40 (s, 9H).

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

    [0404] ##STR00066##

    [0405] A solution of tert-butyl 2-(5-(benzyloxy)-2,3-dihydro-1H-inden-4-yl)acetate (1.82 g, 5.38 mmol, 1 eq) in 2,2,2-trifluoroethanol (50 mL) was bubbled through with nitrogen for 20 minutes. After that, Pd/C (10 wt % loading, matrix activated carbon support, 0.57 g, 538 mol, 0.1 eq) was added and the flask was charged with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere. After 1.5 hours of stirring, another batch of Pd/C (10 wt % loading, matrix activated carbon support, 0.57 g, 538 mol, 0.1 eq) was added. After stirring over the weekend, the reaction mixture was filtered over Celite, and the residue was washed extensively with ethyl acetate. The filtrates were combined and concentrated in vacuo to afford the title compound (1.28 g, 5.15 mmol, 95%).

    [0406] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.33 (bs, 1H), 7.01 (d, 1H), 6.76 (d, 1H), 3.57 (s, 2H), 2.88 (td, 4H), 2.15-1.96 (m, 2H), 1.46 (s, 9H).

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

    [0407] ##STR00067##

    [0408] 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%).

    [0409] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.17 (d, 1H), 7.07 (d, 1H), 3.63 (s, 2H), 2.92 (dt, 4H), 2.14 (p, 2H),1.44 (s, 9H).

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

    [0410] ##STR00068##

    [0411] A suspension of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.08 g, 4.57 mmol, 1 eq), tert-butyl 2-(5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1H-inden-4-yl)acetate (1.74 g, 4.57 mmol, 1 eq) and potassium carbonate (1.90 g, 13.7 mmol, 3 eq) in 1,4-dioxane (25 mL) was bubbled through with nitrogen for 20 minutes. After that, [1,1-bis(diphenylphosphino)ferrocene] dichloro palladium (II) (167 mg, 229 mol, 0.05 eq) was added and the reaction mixture was heated to 80 C. After stirring overnight, another batch of [1,1-bis(diphenylphosphino)ferrocene] dichloro palladium (II) (167 mg, 229 mol, 0.05 eq) was added and the temperature of the reaction mixture was increased to 100 C. After 2 more hours of stirring, another batch of [1,1-bis(diphenylphosphino)ferrocene] dichloro palladium (II) (167 mg, 229 mol, 0.05 eq) was added. After stirring for 20 more hours, another batch of [1,1-bis(diphenylphosphino)ferrocene] dichloro palladium (II) (167 mg, 229 mol, 0.05 eq) was added. After 3 more hours of stirring, the reaction mixture was cooled to room temperature and then filtered. The residue was washed with ethyl acetate and dichloromethane. The filtrates were combined and concentrated in vacuo. The crude product was submitted to normal phase flash chromatography using heptane and ethyl acetate as eluent to afford the title compound (358 mg, 1.05 mmol, 23%).

    [0412] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.16 (d, 1H), 7.19 (d, 1H), 7.03 (d, 1H), 6.86 (dd, 1H), 6.71 (s, 1H), 3.97 (d, 3H), 3.46 (s, 2H), 2.99 (t, 2H), 2.90 (t, 2H), 2.13 (p, 2H), 1.42 (s, 9H).

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

    [0413] ##STR00069##

    [0414] A solution of tert-butyl 2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetate (172 mg, 507 mol, 1 eq) in trifluoroacetic acid (1 mL, 13 mmol, 26 eq) was stirred at room temperature. After for 20 hours, more trifluoroacetic acid (0.5 mL, 6.5 mmol, 13 eq) was added. After 2 more hours, the solution was concentrated in vacuo. The crude product was suspended in toluene and then concentrated again; this was performed 3 times to afford the title compound (180 mg, 506 mol, 89%).

    [0415] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.23 (dd, 1H), 7.32-7.23 (m, 1H), 7.23-6.99 (m, 3H), 4.07 (s, 3H), 3.59 (s, 2H), 2.97 (dt, 4H), 2.14 (p, 2H).

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

    [0416] ##STR00070##

    [0417] To a solution of 2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid, trifluoroacetic acid salt (219 mg, 0.55 mmol, 1 eq) in anhydrous dichloromethane (10 mL) was added one drop of dimethylformamide and then dropwise oxalyl chloride (145 L, 1.65 mmol, 3 eq) at room temperature. After stirring for 2 hours, the reaction mixture was concentrated in vacuo. The crude product was used in the next step without any purification.

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

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

    [0418] ##STR00071##

    [0419] 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 (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%).

    [0420] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.63 (d, 1H), 7.13 (d, 1H), 3.92 (d, 2H), 2.90 (dt, 4H), 2.04 (p, 2H), 1.42 (s, 9H), 1.32 (s, 12H).

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

    [0421] ##STR00072##

    [0422] 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%).

    [0423] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.71 (dd, 1H), 7.72 (dd, 1H), 7.52 (dd, 1H), 7.24 (d, 1H), 7.01 (d, 1H), 3.42 (s, 2H), 3.01 (t, 2H), 2.92 (t, 2H), 2.15 (p, 2H), 1.43 (s, 9H).

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

    [0424] ##STR00073##

    [0425] 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.

    [0426] .sup.1H NMR (of 2-(5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid) (300 MHz, CDCl.sub.3) 8.78 (d, 1H), 7.74 (d, 1H), 7.58 (dd, 1H), 7.34-7.25 (m, 1H), 7.03 (d, 1H), 3.58 (d, 2H), 3.04 (d, 2H), 2.94 (t, 2H), 2.17 (p, 2H).

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

    [0427] ##STR00074##

    [0428] To a solution of 2-(5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetic acid (non salt form) (34 mg, 0.12 mmol, 1 eq) in anhydrous dichloromethane (2 mL) was added one drop of dimethylformamide and after that dropwise oxalyl chloride (32 L, 0.37 mmol, 3 eq) at room temperature. After stirring for 1 hour, the volatiles were removed in vacuo and the crude product was used for the following step without any purification.

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

    [0429] ##STR00075##

    [0430] 2-(4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetic acid, TFA salt (Intermediate A1) (61 mg, 0.2 mmol) was stirred in DCM (10 mL) and one drop of dimethylformamide was added followed by the dropwise addition of oxalylchloride (88 L, 1 mmol). The solution was stirred at room temperature for 4 hours and then concentrated thoroughly to afford the title compound (65 mg, 99%) as a yellow oil.

    [0431] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.04 (s, 1H), 7.23-7.11 (m, 2H), 7.04 (s, 1H), 6.88-6.75 (m, 1H), 4.40 (s, 3H), 4.08 (s, 2H), 3.17 (m, 1H), 1.27 (m 6H).

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

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

    [0432] ##STR00076##

    [0433] 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.

    [0434] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.86 (dd, 1H), 6.54 (dd, 1H), 3.94 (s, br, 2H), 3.83 (s, 3H).

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

    [0435] ##STR00077##

    [0436] 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.

    [0437] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.47 (m, 2H), 5.32 (s, 1H), 5.09 (s, 1H), 3.85 (s, 3H), 3.77 (s, br, 2H), 2.07 (s, 3H).

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

    [0438] ##STR00078##

    [0439] A mixture of 4-fluoro-2-methoxy-6-(prop-1-en-2-yl)aniline (2.0 g, 11 mmol) and Pd/C (%, 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.

    [0440] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.52 (m, 2H), 3.88 (s, 3H), 3.58 (s, br, 2H), 2.95 (m, 1H), 1.29 (d, 6H).

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

    [0441] ##STR00079##

    [0442] 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.

    [0443] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.65 (dd, 1H), 6.51 (dd, 1H), 3.88 (s, 3H), 3.48 (m, 1H), 1.22 (d, 6H).

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

    [0444] ##STR00080##

    [0445] 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.

    [0446] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.61 (dd, 1H), 6.46 (dd, 1H), 3.79 (s, 3H), 3.59 (s, 2H), 3.08 (m, 1H), 1.44 (s, 9H), 1.19 (d, 6H).

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

    [0447] ##STR00081##

    [0448] 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.

    [0449] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.72 (m, 2H), 3.66 (s, 2H), 2.86 (m, 1H), 1.25 (d, 6H).

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

    [0450] ##STR00082##

    [0451] 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.

    [0452] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.61 (dd, 1H), 6.50 (dd, 1H), 3.76 (s, 3H), 3.71 (s, 2H), 3.15 (m, 1H), 1.20 (d, 6H).

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

    [0453] ##STR00083##

    [0454] 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.

    [0455] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.07 (dd, 1H), 6.94 (dd, 1H), 3.77 (s, 2H), 3.71 (s, 3H), 3.09 (m, 1H), 1.21 (d, 6H).

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

    [0456] ##STR00084##

    [0457] 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.

    [0458] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.62 (s, br, 1H), 8.53 (s, br, 1H), 7.63 (d, 1H), 7.34 (m, 1H), 7.05 (dd, 1H), 6.79 (dd, 1H), 3.63 (s, 3H), 3.55 (s, 2H), 3.05 (m, 1H), 1.24 (d, 6H).

    [0459] LCMS: m/z 288 (M+H).sup.+ (ES.sup.+).

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

    [0460] ##STR00085##

    [0461] 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.

    [0462] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.77 (s, br, 1H), 8.57 (s, br, 1H), 7.76 (d, 1H), 7.47 (s, br, 1H), 7.09 (dd, 1H), 6.76 (dd, 1H), 3.49 (s, 2H), 3.18 (m, 1H), 1.28 (d, 6H).

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

    [0463] ##STR00086##

    [0464] 2-(4-Fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetic acid (50 mg, 0.18 mmol) was stirred in DCM (10 mL) and one drop of dimethylformamide was added followed by the dropwise addition of oxalylchloride (48 L, 0.55 mmol). The solution was stirred at room temperature for 4 hours and concentrated thoroughly to afford the title compound (3 mg, 99%) as a yellow oil.

    [0465] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.89 (d, 1H), 8.74 (s, 1H), 8.31 (d, 1H), 8.07 (m, 1H), 7.23-7.16 (m, 1H), 6.85-6.71 (m, 1H), 4.06 (s, 2H), 3.18 (m, 1H), 1.27 (m, 6H).

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

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

    [0466] ##STR00087##

    [0467] 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.

    [0468] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.69 (d, 2H), 7.42 (d, 2H), 6.78 (dd, 1H), 6.72 (dd, 1H), 5.36 (s, 1H), 5.11 (s, 1H), 3.74 (bs, 2H), 2.09 (m, 3H).

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

    [0469] ##STR00088##

    [0470] 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.

    [0471] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.64 (d, 2H), 7.40 (d, 2H), 6.82 (dd, 1H), 6.76 (dd, 1H), 3.61 (bs, 2H),2.91 (m, 1H), 1.25 (d, 6H).

    [0472] LCMS: m/z 231 (M+H).sup.+ (ES.sup.+).

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

    [0473] ##STR00089##

    [0474] 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 (mL). Sodium nitrite (583 mg, 8.45 mmol) in water (1 mL) was added and the reaction mixture was stirred at 0 C. for 45 minutes. Copper(I) bromide (1.10 g, 7.68 mmol) and copper(II) bromide (1.72 g, 7.68 mmol) were added. The reaction mixture was allowed to reach room temperature over 2 hours, poured into saturated sodium carbonate solution (300 mL), and extracted with DCM (2250 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness in vacuo. The title compound (0.85 g, 37%) was obtained as a brown oil.

    [0475] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.66 (d, 2H), 7.28 (d, 2H), 7.05 (dd, 1H), 6.83 (dd, 1H), 3.42 (m, 1H), 1.25 (d, 6H).

    [0476] LCMS: m/z 294 (M+H).sup.+ (ES.sup.+).

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

    [0477] ##STR00090##

    [0478] 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.

    [0479] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.76 (d, 2H), 7.38 (d, 2H), 7.05 (dd, 1H), 6.78 (dd, 1H), 3.43 (s, 2H), 3.04 (m, 1H), 1.40 (s, 9H), 1.23 (d, 6H).

    [0480] 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

    [0481] ##STR00091##

    [0482] 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).

    [0483] .sup.1H NMR (300 MHz, CDCl.sub.3) 9.00 (d, 2H), 7.93 (d, 2H), 7.21 (dd, 1H), 6.81 (dd, 1H), 3.57 (s, 2H), 3.11 (p, 1H),1.27 (d, 6H).

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

    [0484] ##STR00092##

    [0485] To a solution of 2-(4-fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetic acid (non salt form) (54 mg, 0.20 mmol, 1 eq) and one drop of dimethylformamide in anhydrous dichloromethane (8 mL) was added dropwise oxalyl chloride (53 L, 0.60 mmol, 3 eq) at room temperature. The reaction mixture was stirred for 1 hour at room temperature and then concentrated in vacuo. The crude product was used in the next step without purification.

    Intermediate A7: 2-(4-Fluoro-2,6-diisopropylphenyl)acetic acid

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

    [0486] ##STR00093##

    [0487] 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 (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 (2150 mL). The combined organic layers were washed with brine (2200 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.

    [0488] .sup.1H NMR (400 MHz, CDCl.sub.3) 6.68 (d, 2H), 5.32-5.31 (m, 2H), 5.08 (d, 2H), 3.84 (s, 2H) and 2.07 (d, 6H).

    [0489] LCMS: m/z 192.2 (M+H).sup.+ (ES.sup.+).

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

    [0490] ##STR00094##

    [0491] 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.

    [0492] 1H NMR (400 MHz, CDCl.sub.3) 6.76 (d, 2H), 3.56 (s, 2H), 2.99-2.89 (m, 2H) and 1.26 (d, 12H).

    [0493] LCMS: m/z 196.2 (M+H).sup.+ (ES.sup.+).

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

    [0494] ##STR00095##

    [0495] 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. 10 .sup.1H NMR (400 MHz, CDCl.sub.3) 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

    [0496] ##STR00096##

    [0497] 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

    [0498] ##STR00097##

    [0499] 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.

    [0500] .sup.1H NMR (400 MHz, CDCl.sub.3) 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

    [0501] ##STR00098##

    [0502] 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 (3500 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 (3500 mL). The combined organic layers were washed with brine (2200 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.

    [0503] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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 P1:5-((Dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide

    [0504] ##STR00099##

    [0505] N,N,1-Trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P3)(500 mg, 2.15 mmol) was stirred in THF (10 mL) and a solution of borane tetrahydrofuran complex (1M, 6 mL, 6 mmol) was added dropwise. The mixture was stirred overnight at reflux and then allowed to cool to room temperature. A solution of 1M HCl (aqueous, 6 mL) was added dropwise. The reaction mixture was stirred at 50 C. for 2 hours, and then allowed to cool to room temperature, concentrated and stripped with toluene (210 mL). The residue was dissolved in MeOH and loaded on a column of SCX (8 g). The MeOH was removed by suction and the column was washed with MeOH (215 mL). 0.7N NH.sub.3 in MeOH (20 mL) was added to the column. The column was left standing for 5 minutes, and then washed twice more with 0.7N NH.sub.3 in MeOH (215 mL). The combined filtrates were concentrated to afford the title compound (314 mg, 67%) as a white solid.

    [0506] .sup.1H NMR (300 MHz, Chloroform-d) 6.58 (s, 1H), 3.95 (s, 3H), 3.41 (s, 2H), 2.23 (s, 6H).

    Intermediate P2: 1-Cyclopropyl-5-((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide

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

    [0507] ##STR00100##

    [0508] 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 (350 mL). The combined organic layers were washed with brine (233 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (17.7 g, 30%) as a yellow oil.

    [0509] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.54 (d, 1H), 6.84 (d, 1H), 3.73-3.67 (m, 1H), 1.24-1.22 (m, 2H) and 1.13-1.07 (m, 2H).

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

    [0510] ##STR00101##

    [0511] 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). 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 (3500 mL). The combined organic layers were washed with brine (2250 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 30:1 to 1:1) to give the title compound (20 g, 69%) as a yellow oil.

    [0512] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.14 (d, 1H), 5.11 (d, 1H), 3.57 (br s, 2H), 3.38-3.32 (m, 1H), 0.99-0.95 (m, 2H) and 0.90-0.87 (m, 2H).

    [0513] LCMS: m/z 124.2 (M+H).sup.+ (ES.sup.+).

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

    [0514] ##STR00102##

    [0515] 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 (3250 mL). The combined organic layers were washed with brine (2150 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 100:0 to 1:1) to give the title compound (14 g, 44%) as a yellow oil.

    [0516] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.62 (d, 1H), 6.83 (d, 1H), 3.78-3.72 (m, 1H), 1.28-1.24 (m, 2H) and 1.16-1.12 (m, 2H).

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

    [0517] ##STR00103##

    [0518] To a solution of 1-cyclopropyl-1H-pyrazole-3-sulfonyl chloride (28 g, 135.49 mmol, 1 eq) in THF (300 mL) was added TEA (27.42 g, 270.99 mmol, 2 eq) and bis(4-methoxybenzyl)amine (34.87 g, 135.49 mmol, 1 eq). The reaction mixture was stirred at 25 C. for 1 hour, and then diluted with H.sub.2O (500 mL) and extracted with EtOAc (3500 mL). The combined organic layers were washed with brine (2500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by reversed phase flash chromatography (0.5% NH.sub.3.H.sub.2O-MeCN) and the collected eluting solution was concentrated under reduced pressure to remove most of MeCN. Then the mixture was extracted with EtOAc (31). The combined organic layers were washed with brine (2500 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (30 g, 52% yield, 99.8% purity on HPLC).

    [0519] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.49 (d, 1H), 7.08-7.06 (m, 4H), 6.79-6.77 (m, 4H), 6.62 (d, 1H), 4.32 (s, 4H), 3.80 (s, 6H), 3.68-3.64 (m, 1H), 1.15-1.13 (m, 2H) and 1.9-1.06 (m, 2H).

    [0520] 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

    [0521] ##STR00104##

    [0522] 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 (3250 mL). The combined organic layers were washed with brine (2100 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.

    [0523] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

    [0524] LCMS: m/z 485.2 (M+H).sup.+ (ES.sup.+).

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

    [0525] ##STR00105##

    [0526] 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.

    [0527] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

    [0528] LCMS: m/z 245.2 (M+H).sup.+ (ES.sup.+).

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

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

    [0529] ##STR00106##

    [0530] A solution of 1-methyl-1H-pyrazol-3-amine (25 g, 257.42 mmol, 1 eq) in MeCN (600 mL) at 0 C. was treated with concentrated HCl (60 mL) in H.sub.2O (60 mL). Then an aqueous solution of NaNO.sub.2 (21-31 g, 308.90 mmol, 1.2 eq) in H.sub.2O (60 mL) was added slowly. The resulting reaction mixture was stirred at 0 C. for 40 minutes. AcOH (60 mL), CuCl.sub.2 (17.31 g, 128.71 mmol, 0.5 eq) and CuCl (1.27 g, 12.87 mmol, 0.05 eq) were added. Then SO.sub.2 gas (15 psi) was bubbled into the reaction mixture at 0 C. for 15 minutes. The reaction mixture was stirred at 0 C. for 20 minutes, and then concentrated in vacuo to remove most MeCN. Then the reaction mixture was quenched by addition of H.sub.2O (0.6 L) and extracted with EtOAc (20.3 L). The combined organic layers were washed with brine (30.5 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 20:1 to 10:1) to give the title compound (16.45 g, 35%) as a yellow oil.

    [0531] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.52 (d, 1H), 6.89 (d, 1H) and 4.07 (s, 3H).

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

    [0532] ##STR00107##

    [0533] To a solution of bis(4-methoxybenzyl)amine (99.83 g, 387.96 mmol, 0.91 eq) in THF (1 L) was added TEA (86.28 g, 852.65 mmol, 2 eq), followed by 1-methyl-H-pyrazole-3-sulfonyl chloride (77 g, 426.33 mmol, 1 eq). The reaction mixture was stirred at 25 C. for 12 hours, and then concentrated in vacuo to remove most of THF. The reaction mixture was quenched by addition of 1M aqueous HCl solution (500 mL) and then extracted with EtOAc (2500 mL). The combined organic layers were washed with brine (2600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was triturated with a mixture of petroleum ether and ethyl acetate (70 mL, v:v=5:1) to give the title compound (138 g, 81%) as a white solid.

    [0534] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.40 (d, 1H), 7.08 (d, 4H), 6.78 (d, 4H), 6.65-6.63 (m, 1H), 4.32 (s, 4H), 3.98 (s, 3H) and 3.79 (s, 6H).

    [0535] LCMS: m/z 402.2 (M+H).sup.+ (ES.sup.+).

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

    [0536] ##STR00108##

    [0537] A solution of N,N-bis(4-methoxybenzyl)-1-methyl-1H-pyrazole-3-sulfonamide (100 g, 249.08 mmol, 1 eq) in THF (1.35 L) was cooled to 70 C. Then n-BuLi (2.5 M, 104.61 mL, in THF, 1.05 eq) was added dropwise. The reaction mixture was stirred at 70 C. for 1 hour. Then CO.sub.2 (15 psi) was bubbled into the mixture for 15 minutes. The reaction mixture was stirred at 70 C. for another 1 hour. Then the reaction mixture was quenched with H.sub.2O (1.2 L) and adjusted with 1M aqueous HCl solution to pH 3. Then the reaction mixture was extracted with EtOAc (21 L), washed with brine (21 L), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and ethyl acetate (300 mL, v:v=1:1) to give the title compound (94 g, 84% yield, 99% purity on LCMS) as a white solid.

    [0538] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 6.98-7.16 (m, 5H), 6.82 (d, 4H), 4.25 (s, 4H), 4.15 (s, 3H) and 3.72 (s, 6H).

    [0539] LCMS: m/z 468.2 (M+Na)+(ES.sup.+).

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

    [0540] ##STR00109##

    [0541] To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1-methyl-1H-pyrazole-5-carboxylic acid (100 g, 224.47 mmol, 1 eq), DIPEA (58.02 g, 448.95 mmol, 2 eq) and dimethylamine (2 M, 448.95 mL, in THF, 4 eq) in DMF (1 L) was added T3P (285.69 g, 448.95 mmol, 50% purity in EtOAc, 2 eq) at 25 C. The reaction mixture was stirred for 30 minutes. Then the reaction mixture was quenched by addition of H.sub.2O (2 L) and extracted with EtOAc (21.1 L). The combined organic layers were washed with brine (21.2 L), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was triturated with a mixture of ethyl acetate and petroleum ether (150 mL, v:v=5:1) to give the title compound (92.7 g, 87% yield, 100% purity on LCMS).

    [0542] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.09 (d, 4H), 6.78 (d, 4H), 6.63-6.70 (m, 1H), 4.32 (s, 4H), 4.02 (s, 3H), 3.79 (s, 6H) and 3.11 (d, 6H).

    [0543] LCMS: m/z 473.3 (M+H).sup.+ (ES.sup.+).

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

    [0544] ##STR00110##

    [0545] To a solution of 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide (80 g, 169.29 mmol, 1 eq) in DCM (180 mL) was added TFA (381.33 g, 3.34 mol, 19.75 eq). The reaction mixture was stirred at 15 C. for 15 hours, and then concentrated in vacuo. The residue was re-dissolved in dichloromethane (200 mL). The resulting mixture was treated with MeOH (1.2 L) and a solid was precipitated. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was re-dissolved in dichloromethane (150 mL). The resulting mixture was treated with tert-butyl methyl ether (700 mL) and a solid was precipitated. The suspension was filtered and the filter cake was dried to give the title compound (32 g, 81%) as a white solid.

    [0546] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.50 (s, 2H), 6.81 (s, 1H), 3.89 (s, 3H) and 3.02 (d, 6H).

    [0547] LCMS: m/z 233.2 (M+H).sup.+ (ES.sup.+).

    Intermediate P4: 1-(2-(Dimethylamino)ethyl)-1H-pyrazole-3-sulfonamide

    Step A: Lithium 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate

    [0548] ##STR00111##

    [0549] To a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (100 g, 657.06 mmol, 1 eq) in THF (1.38 L) was added n-BuLi (2.5 M, 276 mL, in THF, 1.05 eq) slowly while keeping the temperature at 70 C. The reaction mixture was stirred for 1.5 hours. Then SO.sub.2(15 psi) was bubbled into the mixture for 15 minutes. After the reaction mixture was heated to 25 C., a solid was formed. The reaction mixture was concentrated in vacuo. The residue was triturated with tert-butyl methyl ether (400 mL) and the mixture was filtered. The filter cake was washed with tert-butyl methyl ether (50 mL), n-hexane (50 mL) and dried to afford the title compound (142 g, crude) as a white solid.

    [0550] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.28 (d, 1H), 6.16 (d, 1H), 5.97 (dd, 1H), 3.92-3.87 (m, 1H), 3.61-3.53 (m, 1H), 2.25-2.18 (m, 1H), 1.98-1.93 (m, 1H), 1.78-1.74 (m, 1H) and 1.52-1.49 (m, 3H).

    [0551] LCMS: m/z 215 (M-Li).sup. (ES.sup.).

    Step B: 1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonyl chloride

    [0552] ##STR00112##

    [0553] To a suspension of lithium 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate (20 g, 90.01 mmol, 1 eq) in DCM (250 mL) was added NCS (12.02 g, 90.01 mmol, 1 eq) while cooling in an ice bath. The reaction mixture was stirred at 0 C. for 2 hours. Then the reaction mixture was quenched with water (100 mL) and partitioned between DCM (300 mL) and water (200 mL). The organic layer was washed with water (200 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound (15.8 g, 63.02 mmol, 70%) as a yellow oil, which was used directly in the next step.

    Step C: N,N-bis(4-Methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonamide

    [0554] ##STR00113##

    [0555] To a mixture of bis(4-methoxybenzyl)amine (16.01 g, 62.23 mmol, 1.04 eq) and TEA (19.33 g, 190-99 mmol, 3.19 eq) in DCM (300 mL) was added a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonyl chloride (15 g, 59.83 mmol, 1 eq) in DCM (so mL) at 0 C. The reaction mixture was stirred at 0 C. for 1 hour and then quenched with water (250 mL). The organic layer was washed with water (250 mL), 1M aqueous HCl solution (2250 mL), water (250 mL), and then dried over anhydrous MgSO.sub.4, filtered, and concentrated in vacuo to give the title compound (25.5 g, 83% yield, 92% purity on LCMS) as a brown oil.

    [0556] LCMS: m/z 494 (M+Na)+(ES.sup.+).

    Step D: N,N-bis(4-Methoxybenzyl)-1H-pyrazole-5-sulfonamide

    [0557] ##STR00114##

    [0558] To a solution of N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonamide (25 g, 53.01 mmol, 1 eq) in THF (183 mL) and MeOH (37 mL) was added a 1M aqueous HCl solution (18.29 mL). The reaction mixture was stirred at 25 C. for 1 hour. Then the reaction mixture was concentrated in vacuo and the residue was partitioned between DCM (200 mL) and H.sub.2O (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous MgSO.sub.4, filtered and concentrated in vacuo. The residue was triturated with tert-butyl methyl ether (100 mL), filtered and dried to give the title compound (12.2 g, 58% yield, 97% purity on LCMS) as a white solid.

    [0559] .sup.1H NMR (400 MHz, CDCl.sub.3) 13.82-13.70 (br s, 1H), 7.92 (d, 1H), 7.07-7.01 (m, 4H), 6.78-6.75 (m, 4H), 6.61 (d, 1H), 4.34 (s, 4H) and 3.80 (s, 6H).

    [0560] LCMS: m/z 410 (M+Na)+(ES.sup.+).

    Step E: 1-(2-Hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0561] ##STR00115##

    [0562] A mixture of N,N-bis(4-methoxybenzyl)-1H-pyrazole-5-sulfonamide (12 g, 30.97 mmol, 1 eq) and K.sub.2CO.sub.3 (8.39 g, 60.70 mmol, 1.96 eq) was suspended in MeCN (150 mL) under a nitrogen atmosphere. 2-Bromoethanol (5.03 g, 40.26 mmol, 1.3 eq) was added and then the resulting mixture was heated to 60 C. for 17 hours. The reaction mixture was quenched with water (500 mL) and extracted with DCM (400 mL). The organic layer was separated and washed with brine (300 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, 30:1 to 1:1) to give the title compound (8 g, 58% yield, 97% purity on LCMS) as a yellow oil.

    [0563] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.55 (d, 1H), 7.04-7.02 (m, 4H), 6.77-6.74 (d, 4H), 6.06 (d, 1H), 4.29 (s, 4H), 4.26-4.23 (t, 2H), 3.93-3.81 (m, 2H) and 3.69 (s, 6H).

    [0564] LCMS: m/z 454 (M+Na)+(ES.sup.+).

    Step F: 2-(3-(N,N-bis(4-Methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)ethyl methanesulfonate

    [0565] ##STR00116##

    [0566] To a solution of 1-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (7 g, 16.22 mmol, 1 eq) and DIPEA (2.94 g, 22.71 mmol, 1.4 eq) in anhydrous DCM (116 mL) was added MsCl (2.23 g, 19.47 mmol, 1.2 eq) under nitrogen. The reaction mixture was stirred at 25 C. for 20 minutes. Then the reaction mixture was quenched with saturated aqueous NaHCO.sub.3 solution (50 mL) and water (30 mL). The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (8.3 g, crude) as a yellow oil, which was used directly in the next step.

    Step G: 1-(2-(Dimethylamino)ethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

    [0567] ##STR00117##

    [0568] To a solution of dimethylamine in THF (2 M, 243 mL, 29.95 eq) was added 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-1H-pyrazol-1-yl)ethyl methanesulfonate (8.27 g, 16.23 mmol, 1 eq). The reaction mixture was heated to 60 C. for 17 hours, and then concentrated in vacuo. The residue was treated with EtOAc (10 mL. The mixture was stirred and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 0:1) to give the title compound (6.5 g, 83% yield, 95% purity on LCMS) as a yellow oil.

    [0569] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.55 (d, 1H), 7.09-7.06 (m, 4H), 6.81-6.78 (m, 4H), 6.65 (d, 1H), 4.31 (s, 4H), 4.31-4.27 (m, 2H), 3.80 (s, 6H), 2.77 (t, 2H) and 2.29 (m, 6H).

    [0570] LCMS: m/z 459 (M+H).sup.+ (ES.sup.+).

    Step H: 1-(2-(Dimethylamino)ethyl)-1H-pyrazole-3-sulfonamide

    [0571] ##STR00118##

    [0572] To a solution of 1-(2-(dimethylamino)ethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (5.5 g, 11.99 mmol, 1 eq) in DCM (10 mL) was added TFA (77.00 g, 675.32 mmol, 56.31 eq). The reaction mixture was stirred at 25 C. for 17 hours, and then concentrated in vacuo. The residue was dissolved in a mixture of dichloromethane (10 mL) and MeOH (200 mL). The resulting mixture was stirred and filtered. Basic resin (Amberlyst A-21, ion exchange resin) was added to the reaction mixture until the pH was 8. Then the reaction mixture was stirred at 25 C. for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was recrystallized from DCM (15 mL) to give the title compound (2.2 g, 84% yield, 100% purity on LCMS).

    [0573] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.86 (d, 1H), 7.37 (br s, 2H), 6.55 (d, 1H), 4.24 (t, 2H), 2.65 (t, 2H) and 2.16 (s, 6H).

    [0574] LCMS: m/z 219 (M+H).sup.+ (ES.sup.+).

    Synthesis of Examples

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

    [0575] ##STR00119##

    [0576] Et.sub.3N (0.67 mL, 4.80 mmol) and 5-((dimethylamino)methyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (60 mg, 0.24 mmol) were added to a solution of 2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetyl chloride (56 mg, 0.24 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 (20 mg, 18%) as a white solid.

    [0577] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.07 (s, 1H), 6.78 (s, 1H), 4.82 (m, 1H), 3.62 (s, 2H), 3.43 (s, 2H), 2.89 (t, 4H), 2.71 (t, 4H), 2.22 (s, 6H), 2.07 (m, 4H), 1.47 (d, 7H).

    [0578] LCMS: m/z 445 (M+H).sup.+ (ES.sup.+); 443 (MH).sup. (ES.sup.).

    Example 2: 3-(N-(2-(4-Fluoro-2,6-diisopropylphenyl)acetyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide

    [0579] ##STR00120##

    [0580] To a mixture of N,N,1-trimethyl-3-sulfamoyl-H-pyrazole-5-carboxamide (Intermediate P3) (60 mg, 258.33 mol, 1 eq) and 2-(4-fluoro-2,6-diisopropylphenyl)acetic acid (Intermediate A7) (62 mg, 258.33 mol, 1 eq) in DCM (1 mL) and DMF (1 mL) was added EDC (99 mg, 516.66 mol, 2 eq) and DMAP (63 mg, 516.66 mol, 2 eq) under nitrogen. The reaction mixture was stirred at 15 C. for 2 hours. Then the reaction mixture was quenched with 1M aqueous HCl solution (1.5 mL) and extracted with DCM (22 mL). The organic layers were washed with brine (23 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (Column: Phenomenex Synergi C18, 150 mm*25 mm*10 m; mobile phase [A: water (0.1% TFA); B: MeCN]; B %: 42%-72%, 9 min) to give the title compound (49.40 mg, 42% yield, 100% purity on LCMS) as a white solid.

    [0581] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.51 (s, 1H), 7.01 (s, 1H), 6.88 (d, 2H), 3.91 (s, 3H) 3.78 (s, 2H) 2.98 (s, 6H) 2.92-2.87 (m, 2H) and 1.04 (d, 12H).

    [0582] LCMS: m/z 453.3 (M+H).sup.+ (ES.sup.+).

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

    [0583] ##STR00121##

    [0584] Prepared as described for N-((5-((dimethylamino)methyl)-1-isopropyl-1H-pyrazol-3-yl)sulfonyl)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetamide (Example 1) using 5-(1-(dimethylamino)ethyl)-1-isopropyl-1H-pyrazole-3-sulfonamide, trifluoroacetate salt (110 mg, 0.29 mmol) and 2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetyl chloride (60 mg, 0.26 mmol) to afford the title compound (31 mg, 26%) as a white solid.

    [0585] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.07 (s, 1H), 6.75 (s, 1H), 4.90 (m, 1H), 3.80 (q, 1H), 3.62 (s, 2H), 2.89 (t, 4H), 2.71 (t, 4H), 2.18 (s, 6H), 2.07 (m, 4H), 1.45 (t, 6H), 1.33 (d, 3H).

    [0586] LCMS: m/z 458 (M+H).sup.+ (ES.sup.+); 457 (MH).sup. (ES.sup.).

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

    [0587] ##STR00122##

    [0588] N,N,1-trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P3) (93 mg, 0.4 mmol) and Et.sub.3N (0.11 mL, 0.8 mmol) were stirred in DCM (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride (Intermediate A4) (64 mg, 0.2 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature and then concentrated. The residue was dissolved in DMSO (0.5 mL) and KO.sup.tBu (45 mg, 0.4 mmol) was added. The mixture was filtered over cotton wool and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (8 mg, 8%) as a white solid.

    [0589] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.07 (dd, 1H), 7.02 (dd, 1H), 6.90 (dd, 1H), 6.84 (s, 1H), 6.78 (dd, 1H), 6.72 (dd, 1H), 3.92 (d, 6H), 3.47 (s, 2H), 3.14 (m, 1H), 3.13 (dd, 6H), 1.14 (d, 6H).

    [0590] LCMS: m/z 518 (M+H).sup.+ (ES.sup.+).

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

    [0591] ##STR00123##

    [0592] N,N,1-trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P3) (84 mg, 0.36 mmol) and Et.sub.3N (0.1 mL, 0.72 mmol) were stirred in DCM (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(pyridin-3-yl)phenyl)acetyl chloride (Intermediate A5) (53 mg, 0.18 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature and then concentrated. The residue was dissolved in DMSO (0.5 mL). The mixture was filtered over cotton wool and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford crude product (10 mg). The crude product was subjected to preparative HPLC (see Experimental Methods, Purification Method 2) to afford the title compound (4 mg, 5%) as a white solid.

    [0593] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.53 (d, 1H), 8.43 (s, 1H), 7.75 (d, 1H), 7.44 (dd, 1H), 7.07 (dd, 1H), 6.92 (s, 1H), 6.78 (dd, 1H), 3.97 (s, 3H), 3.49 (s, 2H), 3.10 (d, 6H), 3.08 (m, 1H), 1.16 (d, 6H).

    [0594] LCMS: m/z 488 (M+H).sup.+ (ES.sup.+); 486 (MH).sup. (ES.sup.).

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

    [0595] ##STR00124##

    [0596] To a solution of N,N,1-trimethyl-3-sulfamoyl-H-pyrazole-5-carboxamide (Intermediate P3) (48 mg, 0.2 mmol, 2 eq) and triethylamine (29 L, 0.2 mmol, 2 eq) in anhydrous dichloromethane (2.5 mL) cooled in an ice bath was added dropwise a solution of 2-(4-fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetyl chloride (Intermediate A6) (30 mg, 0.1 mmol, 1 eq) in anhydrous dichloromethane (2.5 mL). After complete addition, the ice bath was removed and the reaction mixture was stirred at room temperature. After 2 hours, the reaction mixture was concentrated in vacuo. The crude product was suspended in tetrahydrofuran, then potassium tert-butoxide (23 mg, 0.2 mmol, 2 eq) was added. After stirring for 5 minutes, the suspension was concentrated in vacuo. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (7.6 mg, 0.014 mmol, 14%) as a white solid.

    [0597] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.55-8.44 (m, 2H), 7.43-7.30 (m, 2H), 7.06 (dd, 1H), 6.84 (s, 1H), 6.76 (dd, 1H), 3.95 (s, 3H), 3.44 (s, 2H), 3.36-3.33 (m, 1H), 3.10 (d, 6H), 1.15 (d, 6H).

    [0598] LCMS: m/z 489 (M+H).sup.+ (ES.sup.+).

    Example 7: N-((1-(1-(Dimethylamino)-2-methylpropan-2-yl)-1H-pyrazol-3-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetamide, potassium salt

    [0599] ##STR00125##

    [0600] To a suspension of 1-(1-(dimethylamino)-2-methylpropan-2-yl)-1H-pyrazole-3-sulfonamide (51 mg, 0.2 mmol, 2 eq) in anhydrous tetrahydrofuran (2 mL) was added potassium tert-butoxide (23 mg, 0.2 mmol, 2 eq). The suspension was stirred for 30 minutes at room temperature and then cooled in an ice bath. A solution of 2-(4-fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetyl chloride (Intermediate A6) (30 mg, 0.1 mmol, 1 eq) in anhydrous tetrahydrofuran (2 mL) was added. After complete addition, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After stirring over the weekend, the reaction mixture was concentrated in vacuo. The crude product was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (2 mg, 4 mol, 4%).

    [0601] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.53-8.47 (m, 2H), 7.74 (d, 1H), 7.46-7.37 (m, 2H), 7.05 (dd, 1H), 6.75 (dd, 1H), 6.63 (d, 1H), 3.43 (s, 2H), 3.19-3.11 (m, 1H), 2.81 (s, 2H), 2.09 (s, 6H), 1.59 (s, 6H), 1.17 (d, 6H).

    [0602] LC-MS: m/z 503 (M+H).sup.+ (ES.sup.+).

    Example 8: N-((5-((Dimethylamino)methyl)-1-methyl-1H-pyrazol-3-yl) sulfonyl)-2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) acetamide, potassium salt

    [0603] ##STR00126##

    [0604] 5-((Dimethylamino)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate P1) (70 mg, 0.32 mmol) and KO.sup.tBu (54 mg, 0.48 mmol) were stirred in THF (6 mL). A solution of 2-(4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl)acetyl chloride (Intermediate A4) (51 mg, 0.16 mmol) in THF (1 mL) was added dropwise. The mixture was stirred overnight at room temperature and concentrated. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (24 mg, 30%) as a white solid.

    [0605] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.06 (dd, 1H), 7.02 (dd, 1H), 6.91 (dd, 1H), 6.79 (dd, 1H), 6.72 (dd, 1H), 6.55 (s, 1H), 3.90 (d, 6H), 3.47 (d, 4H), 3.17-3.02 (m, 1H), 2.24 (s, 6H), 1.14 (d, 6H).

    [0606] LCMS: m/z 504 (M+H).sup.+ (ES.sup.+); 502 (MH).sup. (ES.sup.).

    Example A: 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

    [0607] ##STR00127##

    [0608] 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.

    [0609] .sup.1H NMR (300 MHZ, CDCl.sub.3) 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).

    [0610] LCMS: m/z 457 (M+H).sup.+ (ES.sup.+); 455 (MH).sup. (ES.sup.).

    Example 10: N-((1-Cyclopropyl-5-((dimethylamino)methyl)-1H-pyrazol-3-yl)sulfonyl)-2-(4-fluoro-2,6-diisopropylphenyl)acetamide

    [0611] ##STR00128##

    [0612] To a solution of 1-cyclopropyl-5-((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide (Intermediate P2) (70 mg, 286.52 mol, 1 eq) in DCM (1 mL) and DMF (1 mL) were added EDC (109 mg, 573.03 mol, 2 eq), DMAP (70 mg, 573.03 mol, 2 eq) and 2-(4-fluoro-2,6-diisopropylphenyl)acetic acid (Intermediate A7) (68 mg, 286.52 mol, 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 (35 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 m; 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.

    [0613] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 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).

    [0614] LCMS: m/z 465.3 (M+H).sup.+ (ES.sup.+).

    Example 11: N-((5-(1-(Dimethylamino)ethyl)-1-methyl-1H-pyrazol-3-yl) sulfonyl)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetamide

    [0615] ##STR00129##

    [0616] Prepared as described for N-((5-((dimethylamino)methyl)-1-isopropyl-1H-pyrazol-3-yl)sulfonyl)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetamide (Example 1) using 5-(1-(dimethylamino)ethyl)-1-methyl-1H-pyrazole-3-sulfonamide, trifluoroacetate salt (100 mg, 0.30 mmol) and 2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetyl chloride (70 mg, 0.30 mmol). After the purification by column chromatography, the product was still contaminated with sulfonamide starting material. The mixture was dissolved in DMSO (1 mL) and purified by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (10 mg, 8%) as a white solid.

    [0617] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.02 (s, 1H), 6.71 (s, 1H), 3.79-3.69 (m, 4H), 3.58 (s, 2H), 2.85 (t, 4H), 2.68 (s, 4H), 2.17 (s, 6H), 2.02 (m, 4H), 1.30 (d, 3H).

    [0618] LCMS: m/z 431 (M+H).sup.+ (ES.sup.+); 429 (MH).sup. (ES.sup.).

    Example 12: 3-(N-(2-(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)acetyl) sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide

    [0619] ##STR00130##

    [0620] Prepared as described for N-((5-((dimethylamino)methyl)-1-isopropyl-1H-pyrazol-3-yl)sulfonyl)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetamide (Example 1) using N,N,1-trimethyl-3-sulfamoyl-H-pyrazole-5-carboxamide (Intermediate P3) (100 mg, 0.43 mmol) and 2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetyl chloride (100 mg, 0.43 mmol) to afford the title compound (76 mg, 41%) as a white solid.

    [0621] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.87 (s, 1H), 7.10 (s, 1H), 7.07 (s, 1H), 4.08 (s, 3H), 3.61 (s, 2H), 3.18 (s, 3H), 3.14 (s, 3H), 2.91 (t, 4H), 2.72 (t, 4H), 2.10 (m, 4H).

    [0622] LCMS: m/z 431 (M+H).sup.+ (ES.sup.+); 429 (MH).sup. (ES.sup.).

    Example 13: N-((1-(1-(Dimethylamino)-2-methylpropan-2-yl)-1H-pyrazol-3-yl)sulfonyl)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetamide

    [0623] ##STR00131##

    [0624] Prepared as described for N-((5-((dimethylamino)methyl)-1-isopropyl-1H-pyrazol-3-yl)sulfonyl)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetamide (Example 1) using 1-(1-(dimethylamino)-2-methylpropan-2-yl)-1H-pyrazole-3-sulfonamide (55 mg, 0.22 mmol) and 2-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)acetyl chloride (60 mg, 0.26 mmol) to afford the title compound (7 mg, 6%) as a white solid.

    [0625] .sup.1H NMR (300 MHz, Methanol-d.sub.4) 7.75 (s, 1H), 6.85 (s, 1H), 6.63 (s, 1H), 3.48 (s, 2H), 2.98 (s, 2H), 2.79 (q, 8H), 2.19 (s, 6H), 1.99 (m, 4H), 1.60 (s, 6H).

    [0626] LCMS: m/z 445 (M+H).sup.+ (ES.sup.+); 443 (MH).sup. (ES.sup.).

    Example 14: 3-(N-(2-(5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide

    [0627] ##STR00132##

    [0628] A solution of N,N,1-trimethyl-3-sulfamoyl-1H-pyrazole-5-carboxamide (Intermediate P3) (118 mg, 0.51 mmol, 2 eq) and triethylamine (0.21 mL, 1.52 mmol, 6 eq) in dichloromethane (5 mL) was cooled in an ice bath. Then a solution of 2-(5-(2-methoxypyridin-4-yl)-2,3-dihydro-H-inden-4-yl)acetyl chloride (Intermediate A2) (110 mg, 0.25 mmol, 1 eq) in anhydrous dichloromethane (5 mL) was added dropwise. After complete addition, the ice bath was removed and the reaction mixture was stirred at room temperature. After stirring over the weekend, the reaction mixture concentrated in vacuo. The residue was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (23 mg, 46 mol, 18%).

    [0629] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.05 (dd, 1H), 7.12 (d, 1H), 6.97 (d, 1H), 6.91 (dd, 1H), 6.85 (s, 1H), 6.78 (dd, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 3.46 (s, 2H), 3.10 (d, 6H), 2.92 (t, 2H), 2.82 (t, 2H), 2.05 (p, 2H).

    [0630] LC-MS: m/z 498 (M+H).sup.+ (ES.sup.+).

    Example 15: 3-(N-(2-(5-(2-Cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) acetyl)sulfamoyl)-N,N,1-trimethyl-1H-pyrazole-5-carboxamide

    [0631] ##STR00133##

    [0632] To a solution of N,N,1-trimethyl-3-sulfamoyl-H-pyrazole-5-carboxamide (Intermediate P3) (41 mg, 0.18 mmol, 2 eq) in anhydrous dichloromethane (2 mL) was added triethylamine (37 L, 0.26 mmol, 3 eq). The solution was cooled in an ice bath. A solution of 2-(5-(2-cyanopyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)acetyl chloride (Intermediate A3) (26 mg, 88 mol, 1 eq) in anhydrous dichloromethane (2 mL) was added dropwise. After complete addition, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature. After stirring over the weekend, the reaction mixture was concentrated in vacuo. The crude product was subjected to preparative HPLC (see Experimental Methods, Purification Method 2) to afford the title compound (0.7 mg, 1.0 mol, 2%).

    [0633] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.64 (d, 1H), 7.87 (s, 1H), 7.66 (dd, 1H), 7.17 (d, 1H), 7.01 (d, 1H), 6.84 (s, 1H), 3.94 (s, 3H), 3.42 (s, 2H), 3.10 (m, 4H), 2.15 (s, 6H), 1.88 (m, 2H).

    [0634] LCMS: m/z 493 (M+H).sup.+ (ES.sup.+).

    Example 16: N-((1-(2-(Dimethylamino)ethyl)-1H-pyrazol-3-yl)sulfonyl)-2-(4-fluoro-2,6-diisopropylphenyl)acetamide

    [0635] ##STR00134##

    [0636] To a solution of 2-(4-fluoro-2,6-diisopropylphenyl)acetic acid (Intermediate A7) (60 mg, 251.79 mol, 1 eq) and 1-(2-(dimethylamino)ethyl)-1H-pyrazole-3-sulfonamide (Intermediate P4) (66 mg, 302.14 mol, 1.2 eq) in DMF (1 mL) was added EDC (97 mg, 503.57 mol, 2 eq) and DMAP (62 mg, 503.57 mol, 2 eq). The reaction mixture was stirred at 16 C. for 3 hours. Then the reaction mixture was poured into water (50 mL) and adjusted to pH 9 with saturated aqueous Na.sub.2CO.sub.3 solution (50 mL). The mixture was extracted with EtOAc (380 mL). The organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (0.01% TFA-MeCN) and then purified by prep-HPLC (Column: Waters Xbridge C18, 150 mm*25 mm*5 m; mobile phase [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 12%-42%,11.5 min) to give the title compound (11.88 mg, 11% yield, 100% purity on LCMS) as a light yellow solid.

    [0637] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.85 (d, 1H), 6.85 (d, 2H), 6.62 (d, 1H), 4.31-4.26 (m, 2H), 3.67 (s, 2H), 3.02-2.94 (m, 2H), 2.77 (t, 2H), 2.25 (s, 6H), and 1.05 (d, 12H).

    [0638] LCMS: m/z 439.2 (M+H).sup.+ (ES.sup.+).

    Example 17: N-((5-((Dimethylamino)methyl)-1-methyl-1H-pyrazol-3-yl)sulfonyl)-2-(4-fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetamide

    [0639] ##STR00135##

    [0640] To a suspension of 5-((dimethylamino)methyl)-1-methyl-H-pyrazole-3-sulfonamide (Intermediate P) (49 mg, 0.22 mmol, 1.5 eq) in anhydrous tetrahydrofuran (2 mL) was added potassium tert-butoxide (1M solution in tetrahydrofuran, 0.23 mL, 0.22 mmol, 1.5 eq). The suspension was stirred for 30 minutes at room temperature and then cooled in an ice bath. To the suspension was added a solution of 2-(4-fluoro-2-isopropyl-6-(pyridin-4-yl)phenyl)acetyl chloride (Intermediate A6) (44 mg, 0.15 mmol, 1 eq) in anhydrous tetrahydrofuran (2 mL). After complete addition, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After stirring overnight, the reaction mixture was concentrated in vacuo. The crude product was dissolved in DMSO (0.5 mL) and submitted for purification by reversed phase column chromatography (see Experimental Methods, Purification Method 1) to afford the title compound (2.0 mg, 4.2 mol, 3%).

    [0641] .sup.1H NMR (300 MHz, CD.sub.3OD) 8.52-8.47 (m, 2H), 7.44-7.35 (m, 2H), 7.05 (dd, 1H),6.76 (dd, 1H), 6.54 (s, 1H), 3.89 (d, 2H), 3.50 (s, 3H), 3.42 (s, 2H), 3.15-3.03 (m, 1H), 2.25 (s, 6H), 1.13 (d, 6H).

    [0642] LC-MS: m/z 474 (M+H).sup.+ (ES.sup.+).

    [0643] The compound of example 18 was synthesised by methods analogous to those outlined above.

    TABLE-US-00007 TABLE 1 .sup.1H NMR and MS data 1H NMR Ex Structure and Name spectrum MS MW 18 [00136]embedded image .sup.1H NMR (300 MHz, Methanol- d.sub.4) 8.07 (dd, 1H), 7.71 (d, 1H), 7.02 (dd, 1H), 6.94 (dd, 1H), 6.81 (dd, 1H), 6.72 (dd, 1H), 6.62 (d, 1H), 3.92 (s, 3H), 3.45 (s, 2H), 3.11 (m, 1H), 2.70 (s, 2H), 2.01 (s, 6H), 1.58 (s, 6H), 1.15 (d, 6H). m/z 532.2 (M + H).sup.+, (ES.sup.+); 530.2 (M H).sup. (ES.sup.). 531.64

    [0644] Further compounds of the invention may be synthesised by methods analogous to those outlined above.

    ExamplesBiological Studies

    NLRP3 and Pyroptosis

    [0645] It is well established that the activation of NLRP3 leads to cell pyroptosis and this feature plays an important part in the manifestation of clinical disease (Yan-gang Liu et al., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al., Hepatology, 2014, 59(3), 898-910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59(5), 1691-1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15-27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366-10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, it is anticipated that inhibitors of NLRP3 will block pyroptosis, as well as the release of pro-inflammatory cytokines (e.g. IL-1) from the cell.

    THP-1 Cells: Culture and Preparation

    [0646] THP-1 cells (ATCC # TIB-202) were grown in RPMI containing L-glutamine (Gibco #11835) supplemented with 1 mM sodium pyruvate (Sigma # S8636) and penicillin (100 units/ml)/streptomycin (0.1 mg/ml) (Sigma # P4333) in 10% Fetal Bovine Serum (FBS) (Sigma # F0804). The cells were routinely passaged and grown to confluency (10.sup.6 cells/ml). On the day of the experiment, THP-1 cells were harvested and resuspended into RPMI medium (without FBS). The cells were then counted and viability (>90%) checked by Trypan blue (Sigma # T8154). Appropriate dilutions were made to give a concentration of 625,000 cells/ml. To this diluted cell solution was added LPS (Sigma # L4524) to give a 1 g/ml Final Assay Concentration (FAC). 40 l of the final preparation was aliquoted into each well of a 96-well plate. The plate thus prepared was used for compound screening.

    THP-1 Cells Pyroptosis Assay

    [0647] The following method step-by-step assay was followed for compound screening. [0648] 1. Seed THP-1 cells (25,000 cells/well) containing 1.0 g/ml LPS in 40 l of RPMI medium (without FBS) in 96-well, black walled, clear bottom cell culture plates coated with poly-D-lysine (VWR #734-0317) [0649] 2. Add 5 l compound (8 points half-log dilution, with 10 M top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells [0650] 3. Incubate for 3 hrs at 37 C., 5% CO.sub.2 [0651] 4. Add 5 l nigericin (Sigma # N7143) (FAC 5 M) to all wells [0652] 5. Incubate for 1 hr at 37 C., 5% CO.sub.2 [0653] 6. At the end of the incubation period, spin plates at 300g for 3 mins and remove supernatant 7. Then add 50 l of resazurin (Sigma # R7017) (FAC 100 M resazurin in RPMI medium without FBS) and incubate plates for a further 1-2 hrs at 37 C. and 5% CO.sub.2 [0654] 8. Plates were read in an Envision reader at Ex 560 nm and Em 590 nm [0655] 9. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

    96-Well Plate Map

    [0656]

    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

    [0657] The results of the pyroptosis assay are summarised in Table 2 below as THP IC.sub.50.

    TABLE-US-00009 TABLE 2 NLRP3 inhibitory activity (1 M = +++, 5 M = ++, 10 M = +) Example THP No IC.sub.50 1 ++ 2 ++ 3 ++ 4 +++ 5 ++ 6 ++ 7 ++ 8 ++ 9 ++ 10 ++ 11 ++ 12 + 13 + 14 + 15 ++ 16 + 17 ++ 18 ++

    [0658] As is evident from the results presented in Table 2, surprisingly in spite of the structural differences versus the prior art compounds, the compounds of the invention show high levels of NLRP3 inhibitory activity.

    [0659] 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.