Sulfonamide carboxamide compounds

Abstract

The present invention relates to compounds of formula (I): wherein Q is selected from O or S; R.sup.1 is a saturated or unsaturated, optionally substituted C.sub.1-C.sub.15 hydrocarbyl group, wherein the atom of R.sup.1 which is attached to the sulfur atom of the sulfonylurea group is not a ring atom of a cyclic group; and R.sup.2 is a cyclic group substituted at the α-position, wherein R.sup.2 may optionally be further substituted. 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): ##STR00101## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Q is O; R.sup.1 is selected from: (a) a branched C.sub.3-C.sub.7 alkyl group, wherein the alkyl group is unsubstituted; or (b) a straight-chained C.sub.2-C.sub.7 alkenyl group, wherein the alkenyl group is unsubstituted; or (c) —(C(R.sup.4).sub.2).sub.nR.sup.3; wherein n is 1 or 2; each R.sup.4 is independently selected from hydrogen, halo, methyl or halomethyl; and R.sup.3 is a phenyl group, wherein the phenyl group may optionally be halo substituted and/or may optionally be substituted with one or two substituents independently selected from C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, —CN, —OR.sup.δ, —COR.sup.δ, or —COOR.sup.δ, wherein each —R.sup.δ is independently selected from hydrogen or a C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, cyclopropyl or halocyclopropyl group, and wherein the group —R.sup.1 including any optional substituents contains from 7 to 12 carbon atoms; or (d) a C.sub.1-C.sub.6 alkyl or C.sub.2-C.sub.6 alkenyl group, wherein the alkyl or alkenyl group is halo substituted and/or is substituted with one, two or three substituents independently selected from —CN, —N.sub.3, —NO.sub.2, —OR.sup.δ, —N(R.sup.δ).sub.2, —COR.sup.δ or —COOR.sup.δ, wherein each —R.sup.δ is independently selected from hydrogen or a C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.3-C.sub.7 halocycloalkyl group; and R.sup.2 is phenyl or a 5- or 6-membered heteroaryl group; wherein (i) the phenyl or 5- or 6-membered heteroaryl group is substituted at the α position with a substituent selected from —R.sup.9, —OR.sup.9 or —COR.sup.9, wherein R.sup.9 is selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group and wherein R.sup.9 is optionally substituted with one or more halo groups; and the phenyl or 5- or 6-membered heteroaryl group is further substituted at the α′ position with a substituent selected from —R.sup.14, —OR.sup.14 or —COR.sup.14, wherein R.sup.14 is selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group and wherein R.sup.14 is optionally substituted with one or more halo groups; and optionally the phenyl or 5- or 6-membered heteroaryl group is further substituted; or (ii) the phenyl or 5- or 6-membered heteroaryl group is substituted with a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring which is fused to the parent phenyl or 5- or 6-membered heteroaryl group across the α,β positions and which is optionally substituted with one or more halo groups; and the phenyl or 5- or 6-membered heteroaryl group is further substituted at the α′ position with a substituent selected from —R.sup.9, —OR.sup.9 or —COR.sup.9, wherein R.sup.9 is selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group and wherein R.sup.9 is optionally substituted with one or more halo groups; and optionally the phenyl or 5- or 6-membered heteroaryl group is further substituted; or (iii) the phenyl or 5- or 6-membered heteroaryl group is substituted with a first cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring which is fused to the parent phenyl or 5- or 6-membered heteroaryl group across the α,β positions and which is optionally substituted with one or more halo groups; and the phenyl or 5- or 6-membered heteroaryl group is substituted with a second cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring which is fused to the parent phenyl or 5- or 6-membered heteroaryl group across the α′,β′ positions and which is optionally substituted with one or more halo groups; and optionally the phenyl group is further substituted; or (iv) the phenyl or 5- or 6-membered heteroaryl group is substituted at the α-position with a monovalent heterocyclic group or a monovalent aromatic group selected from phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl or tetrahydropyranyl, wherein the monovalent heterocyclic or aromatic group may optionally be substituted with one or two substituents independently selected from halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, —R.sup.12—OR.sup.13, —R.sup.12—N(R.sup.13).sub.2, —R.sup.12—CN or —R.sup.12—C≡CR.sup.13, and wherein a ring atom of the monovalent heterocyclic or aromatic group is directly attached to the α-ring atom of the parent phenyl or 5- or 6-membered heteroaryl group; wherein R.sup.12 is independently selected from a bond or a C.sub.1-C.sub.3 alkylene group; and R.sup.13 is independently selected from hydrogen or a C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl group; and the phenyl or 5- or 6-membered heteroaryl group is further substituted at the α′ position with a substituent selected from —R.sup.9, —OR.sup.9 or —COR.sup.9, wherein R.sup.9 is selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group and wherein R.sup.9 is optionally substituted with one or more halo groups; and optionally the phenyl or 5- or 6-membered heteroaryl group is further substituted; or (v) the phenyl or 5- or 6-membered heteroaryl group is substituted at the α-position with a monovalent heterocyclic group or a monovalent aromatic group selected from phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl or tetrahydropyranyl, wherein the monovalent heterocyclic or aromatic group may optionally be substituted with one or two substituents independently selected from halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, —R.sup.12—OR.sup.13, —R.sup.12—N(R.sup.13).sub.2, —R.sup.12—CN or —R.sup.12—C≡CR.sup.13, and wherein a ring atom of the monovalent heterocyclic or aromatic group is directly attached to the α-ring atom of the parent phenyl or 5- or 6-membered heteroaryl group; wherein R.sup.12 is independently selected from a bond or a C.sub.1-C.sub.3 alkylene group; and R.sup.13 is independently selected from hydrogen or a C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl group; and the phenyl or 5- or 6-membered heteroaryl group is further substituted with a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring which is fused to the parent phenyl or 5- or 6-membered heteroaryl group across the α′,β′ positions and which is optionally substituted with one or more halo groups; and optionally the phenyl or 5- or 6-membered heteroaryl group is further substituted; provided the compound of formula (I) is not: ##STR00102##

2. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1, wherein the phenyl or 5- or 6-membered heteroaryl group R.sup.2 is optionally further substituted with halo, —NO.sup.2, —CN, —COOR.sup.15, —CONH.sub.2, —CONHR.sup.15 or —CON(R.sup.15).sub.2, wherein each —R.sup.15 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl group.

3. The compound or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 1.

4. A compound of formula (I): ##STR00103## or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Q is O; R.sup.1 is selected from: (a) a C.sub.1-C.sub.7 alkyl or C.sub.2-C.sub.7 alkenyl group, wherein the alkyl or alkenyl group is unsubstituted; or (b) a C.sub.1-C.sub.6 alkyl or C.sub.2-C.sub.6 alkenyl group, wherein the alkyl or alkenyl group is halo substituted and/or is substituted with one, two or three substituents independently selected from —CN, —N.sub.3, —NO.sub.2, —OR.sup.δ, —N(R.sup.δ).sub.2, —COR.sup.δ or —COOR.sup.δ, wherein each —R.sup.δ is independently selected from hydrogen or a C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.7 cycloalkyl or C.sub.3-C.sub.7 halocycloalkyl group; and R.sup.2 is phenyl or a 5- or 6-membered heteroaryl group selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl or oxadiazolyl; wherein (i) the phenyl or 5- or 6-membered heteroaryl group is substituted at the α-position with a monovalent heterocyclic group or a monovalent aromatic group selected from phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl or tetrahydropyranyl, wherein the monovalent heterocyclic or aromatic group may optionally be substituted with one or two substituents independently selected from halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, —R.sup.12—OR.sup.13, —R.sup.12—N(R.sup.13).sub.2, —R.sup.12—CN or —R.sup.12—C≡CR.sup.13, and wherein a ring atom of the monovalent heterocyclic or aromatic group is directly attached to the α-ring atom of the parent phenyl or 5- or 6-membered heteroaryl group; wherein R.sup.12 is independently selected from a bond or a C.sub.1-C.sub.3 alkylene group; and R.sup.13 is independently selected from hydrogen or a C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl group; and the phenyl or 5- or 6-membered heteroaryl group is further substituted at the α′ position with a substituent selected from —R.sup.9, —OR.sup.9 or —COR.sup.9, wherein R.sup.9 is selected from a C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl or C.sub.2-C.sub.6 cyclic group and wherein R.sup.9 is optionally substituted with one or more halo groups; and optionally the phenyl or 5- or 6-membered heteroaryl group is further substituted; or (ii) the phenyl or 5- or 6-membered heteroaryl group is substituted at the α-position with a monovalent heterocyclic group or a monovalent aromatic group selected from phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl or tetrahydropyranyl, wherein the monovalent heterocyclic or aromatic group may optionally be substituted with one or two substituents independently selected from halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, —R.sup.12—OR.sup.13, —R.sup.12—N(R.sup.13).sub.2, —R.sup.12—CN or —R.sup.12—C≡CR.sup.13, and wherein a ring atom of the monovalent heterocyclic or aromatic group is directly attached to the α-ring atom of the parent phenyl or 5- or 6-membered heteroaryl group; wherein R.sup.12 is independently selected from a bond or a C.sub.1-C.sub.3 alkylene group; and R.sup.13 is independently selected from hydrogen or a C.sub.1-C.sub.3 alkyl or C.sub.1-C.sub.3 haloalkyl group; and the phenyl or 5- or 6-membered heteroaryl group is further substituted with a cycloalkyl, cycloalkenyl, non-aromatic heterocyclic, aryl or heteroaryl ring which is fused to the parent phenyl or 5- or 6-membered heteroaryl group across the α′,β′ positions and which is optionally substituted with one or more halo groups; and optionally the phenyl or 5- or 6-membered heteroaryl group is further substituted.

5. The compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 4, wherein the phenyl or 5- or 6-membered heteroaryl group R.sup.2 is optionally further substituted with halo, —NO.sub.2, —CN, —COOR.sup.15, —CONH.sub.2, —CONHR.sup.15 or —CON(R.sup.15).sub.2, wherein each —R.sup.15 is independently selected from a C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 haloalkyl group.

6. The compound or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 4.

7. A compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the compound is selected from the group consisting of: ##STR00104## ##STR00105## ##STR00106##

8. 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.

9. The pharmaceutical composition as claimed in claim 8, wherein the pharmaceutical composition is a topical pharmaceutical composition.

10. A method of treating, reducing risk of or delaying onset of a disease, disorder or condition in a subject, the method comprising the step of administering an effective amount of the compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1 to the subject, thereby treating, reducing risk of or delaying onset of the disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition and 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; or (xvi) allodynia.

11. A method of treating, reducing risk of or delaying onset of a disease, disorder or condition in a subject, the method comprising the step of administering an effective amount of the compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 1 to the subject, thereby treating, reducing risk of or delaying onset of the disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition and 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); or (xvii) haploinsufficiency of A20 (HA20).

12. The method as claimed in claim 10, wherein the compound is administered as a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

13. 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.

14. 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.

15. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 3, and a pharmaceutically acceptable excipient.

16. The pharmaceutical composition as claimed in claim 15, wherein the pharmaceutical composition is a topical pharmaceutical composition.

17. A method of treating, reducing risk of or delaying onset of a disease, disorder or condition in a subject, the method comprising the step of administering an effective amount of the compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 3 to the subject, thereby treating, reducing risk of or delaying onset of the disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition and 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; or (xvi) allodynia.

18. A method of treating, reducing risk of or delaying onset of a disease, disorder or condition in a subject, the method comprising the step of administering an effective amount of the compound or a pharmaceutically acceptable salt, solvate or prodrug thereof as claimed in claim 3 to the subject, thereby treating, reducing risk of or delaying onset of the disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition and 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); or (xvii) haploinsufficiency of A20 (HA20).

19. The method as claimed in claim 17, 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 3 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 3, and analysing inhibition of NLRP3 or an effect of inhibition of NLRP3 in the cell or non-human animal by the compound.

22. The compound or a pharmaceutically acceptable salt or solvate thereof as claimed in claim 7.

Description

EXAMPLES—COMPOUND SYNTHESIS

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

Abbreviations

(2) 2-MeTHF 2-methyltetrahydrofuran Ac.sub.2O acetic anhydride AcOH acetic acid aq aqueous Boc tert-butyloxycarbonyl br broad Cbz carboxybenzyl CDI 1,1-carbonyl-diimidazole cone concentrated d doublet DABCO 1,4-diazabicyclo [2.2.2]octane DCE 1,2-dichloroethane, also called ethylene dichloride DCM dichloromethane DIPEA N,N-diisopropylethylamine, also called Hünig's base DMA dimethylacetamide DMAP 4-dimethylaminopyridine, also called N,N-dimethylpyridin-4-amine DME dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide 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)+ 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 NaO.sup.tBu sodium tert-butoxide NBS 1-bromopyrrolidine-2,5-dione, also called N-bromosuccinimide NCS 1-chloropyrrolidine-2,5-dione, also called N-chlorosuccinimide NMP N-methylpyrrolidine NMR nuclear magnetic resonance (spectroscopy) Pd(dba).sub.3 tris(dibenzylideneacetone) dipalladium(o) 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 Sept septuplet sat saturated SCX solid supported cation exchange (resin) t triplet T3P propylphosphonic anhydride TBME tert-butyl methyl ether, also called methyl tert-butyl ether TEA triethylamine TFA 2,2,2-trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography wt % weight percent or percent by weight

(3) Experimental Methods

(4) Analytical Methods

(5) NMR spectra were recorded at 300, 400 or 500 MHz (unless stated otherwise) 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 recorded using one of the following machines: An Agilent VNMRS 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, indirect detection probe and direct drive console including PFG module. An Agilent MercuryPlus 300 instrument fitted with a 7.05 Tesla magnet from Oxford instruments, 4 nuclei auto-switchable probe and Mercury plus console. A Bruker 400 MHz spectrometer using ICON-NMR, under TopSpin program control. A Bruker Avance III spectrometer at 400 MHz fitted with a BBO 5 mm liquid probe. A Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe™.

(6) LC-MS Methods: Using SHIMADZU LCMS-2020, Agilent 1200 LC/G1956A MSD and Agilent 1200G6110A, Agilent 1200 LC & Agilent 6110 MSD. Mobile Phase: A: 0.025% NH.sub.3.H.sub.2O in water (v/v); B: acetonitrile. Column: Kinetex EVO C18 2.1×30 mm, 5 μm.

(7) Reversed Phase HPLC Conditions for the LCMS Analytical Methods:

(8) Methods 1a and 1b: Waters Xselect CSH C18 XP column, 2.5 μm (4.6×30 mm) at 40° C.; flow rate 2.5-4.5 mL min.sup.−1 eluted with a water-acetonitrile gradient containing either 0.1% v/v formic acid (Method 1a) or 10 mM ammonium bicarbonate in water (Method 1b) over 4 minutes employing UV detection at 254 nm. Gradient information: 0-3.00 min, ramped from 95% water-5% acetonitrile to 5% water-95% acetonitrile; 3.00-3.01 min, held at 5% water-95% acetonitrile, flow rate increased to 4.5 mL min.sup.−1; 3.01-3.50 min, held at 5% water-95% acetonitrile; 3.50-3.60 min, returned to 95% water-5% acetonitrile, flow rate reduced to 3.50 mL min.sup.−1; 3.60-3.90 min, held at 95% water-5% acetonitrile; 3.90-4.00 min, held at 95% water-5% acetonitrile, flow rate reduced to 2.5 mL min.sup.−1.

(9) HPLC and LC-MS were recorded on an Agilent 1290 series with UV detector and HP 6130 MSD mass detector. Mobile phase A: ammonium acetate (10 mM); water/MeOH/acetonitrile (900:60:40); mobile phase B: ammonium acetate (10 mM); water/MeOH/acetonitrile (100:540:360); column, Waters XBridge BEH C18 XP (2.1×50 mm, 2.5 μm).

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

(11) Pump Program:

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

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

(14) Methods 2a and 2b: Waters BEH C18 (2.1×30 mm, 1.7 μm) at 40° C.; flow rate 0.77 mL min.sup.−1 eluted with a H.sub.2O-MeCN gradient containing either 0.1% v/v formic acid (Method 2a) or 10 mM NH.sub.4HCO.sub.3 in water (Method 2b) over 3 min employing UV detection at 254 nm. Gradient information: 0-0.11 min, held at 95% water-5% acetonitrile, flow rate 0.77 mL min.sup.−1; 0.11-2.15 min, ramped from 95% water-5% acetonitrile to 5% water-95% acetonitrile; 2.15-2.49 min, held at 5% water-95% acetonitrile, flow rate 0.77 mL min.sup.−1; 2.49-2.56 min, returned to 95% water-5% acetonitrile; 2.56-3.00 min, held at 95% water-5% acetonitrile, flow rate reduced to 0.77 mL min.sup.−1.

(15) Purification Methods

(16) Method 1 (acidic preparation): Waters X-Select CSH column C18, 5 m (19×50 mm), flow rate 28 mL/min eluting with a water-acetonitrile gradient containing 0.1% v/v formic acid over 6.5 minutes using UV detection at 254 nm. Gradient information: 0.0-0.2 minutes, 20% acetonitrile; 0.2-5.5 minutes, ramped from 20% acetonitrile to 40% acetonitrile; 5.5-5.6 minutes, ramped from 40% acetonitrile to 95% acetonitrile; 5.6-6.5 minutes, held at 95% acetonitrile.

(17) Method 2 (basic preparation): Waters X-Bridge Prep column C18, 5 μm (19×50 mm), flow rate 28 mL/min eluting with a 10 mM ammonium bicarbonate-acetonitrile gradient over 6.5 minutes using UV detection at 254 nm. Gradient information: 0.0-0.2 minutes, 10% acetonitrile; 0.2-5.5 minutes, ramped from 10% acetonitrile to 40% acetonitrile; 5.5-5.6 minutes, ramped from 40% acetonitrile to 95% acetonitrile; 5.6-6.5 minutes, held at 95% acetonitrile.

(18) Method 3: Phenomenex Gemini column, 10 μm (150×25 mm), flow rate=25 mL/min eluting with a water-acetonitrile gradient containing 0.04% NH.sub.3 at pH 10 over 9 minutes using UV detection at 220 and 254 nm. Gradient information: 0-9 minutes, ramped from 8% to 35% acetonitrile; 9-9.2 minutes, ramped from 35% to 100% acetonitrile; 9.2-15.2 minutes, held at 100% acetonitrile.

(19) Method 4: Buchi Sepracore® X50 system driven by a C-605 pump module, C-620 Sepracore control package, C-640 UV photometer detection unit and C-660 fraction collector.

(20) Revelis C18 reversed-phase 12 g cartridge

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

(22) 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.

(23) Separation Runs:

(24) 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

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

Synthesis of Intermediates

Intermediate A1: 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene

(26) ##STR00032##

(27) To a solution of phosgene (4.45 mL, 20% weight in toluene, 8.4 mmol) in ethyl acetate (90 mL) was added dropwise a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (589 mg, 3.4 mmol) in ethyl acetate (45 mL) at ambient temperature. The resulting reaction mixture was then heated to reflux for 3 hours and upon cooling was filtered and concentrated in vacuo to afford the title compound as a brown oil (756 mg, 100%). The crude product was used directly in the next step without further purification. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 6.8 (s, 1H), 2.89 (m, 8H) and 2.09 (m, 4H).

Intermediate A2: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile

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

(28) ##STR00033##

(29) To a mixture of 2-bromo-4-fluoroaniline (39 g, 205.25 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (36.21 g, 215.51 mmol, 1.05 eq) and K.sub.2CO.sub.3 (70.92 g, 513.12 mmol, 2.5 eq) in dioxane (200 mL) and H.sub.2O (40 mL) was added Pd(dppf)Cl.sub.2 (7.51 g, 10.26 mmol, 0.05 eq) under a nitrogen atmosphere. Then the reaction mixture was stirred at 80° C. for 5 hours. The reaction mixture was quenched by addition of H.sub.2O (600 mL) and extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine (2×600 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate 1:0 to 100:1) to give the title compound (27 g, 77% yield, 89% purity on LCMS) as a yellow oil.

(30) .sup.1H NMR (CDCl.sub.3) δ 6.81-6.76 (m, 2H), 6.66-6.62 (m, 1H), 5.38 (s, 1H), 5.08 (s, 1H), 3.69 (br s, 2H) and 1.25 (s, 3H).

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

Step B: 4-Fluoro-2-isopropylaniline

(32) ##STR00034##

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

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

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

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

(36) ##STR00035##

(37) To a solution of 4-fluoro-2-isopropylaniline (20 g, 130.55 mmol, 1 eq) in toluene (250 mL) was added NBS (23.24 g, 130.55 mmol, 1 eq) at 25° C. The reaction mixture was stirred at 25° C. for 10 minutes. The reaction mixture was poured into H.sub.2O (300 mL) and extracted with EtOAc (2×250 mL). The combined organic phases were washed with brine (2×400 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, eluting only by using petroleum ether) to give the title compound (30 g, 99%) as a black brown oil.

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

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

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

(40) ##STR00036##

(41) To a solution of 2-bromo-4-fluoro-6-isopropylaniline (3.6 g, 15.51 mmol, 1 eq) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (3.60 g, 15.67 mmol, 1.01 eq) in dioxane (90 mL) and H.sub.2O (9 mL) was added Na.sub.2CO.sub.3 (4.11 g, 38.78 mmol, 2.5 eq). Then Pd(dppf)Cl.sub.2 (1.13 g, 1.55 mmol, 0.1 eq) was added to the mixture under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 2 hours under nitrogen. Then the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 20:1 to 5:1) and then triturated with petroleum ether (10 mL) to give the title compound (2.65 g, 65% yield, 97% purity on LCMS) as a yellow solid.

(42) .sup.1HNMR (CDCl.sub.3) δ 8.79 (d, 1H), 7.86 (d, 1H), 7.65 (dd, 1H), 6.99 (dd, 1H), 6.70 (dd, 1H), 3.63 (br s, 2H), 2.98-2.87 (m, 1H) and 1.30 (d, 6H).

(43) LCMS: m/z 256.2 (M+H).sup.+ (ES.sup.+).

Step E: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile

(44) ##STR00037##

(45) To a solution of 4-(2-amino-5-fluoro-3-isopropylphenyl)picolinonitrile (1 g, 3.92 mmol, 1 eq) in THF (40 mL) was added TEA (793 mg, 7.83 mmol, 2 eq). To the above mixture was added triphosgene (465 mg, 1.57 mmol, 0.4 eq) in portions at 5° C. Then the mixture was stirred at 70° C. for 1 hour. The mixture was diluted with EtOAc (200 mL) and then filtered through silica gel. The filtrate was concentrated in vacuo to give the title compound (1.2 g, crude) as a yellow solid, which was used directly in the next step.

Intermediate Ag: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine

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

(46) ##STR00038##

(47) To a solution of 2-bromo-4-fluoro-6-isopropylaniline (12 g, 51.70 mmol, 1 eq) in dioxane (240 mL) and H.sub.2O (48 mL) was added (2-methoxypyridin-4-yl)boronic acid (9.49 g, 62.04 mmol, 1.2 eq) and Na.sub.2CO.sub.3 (13.70 g, 129.26 mmol, 2.5 eq). The reaction mixture was purged with nitrogen three times. Then Pd(dppf)Cl.sub.2 (3.78 g, 5.17 mmol, 0.1 eq) was added to the mixture under a nitrogen atmosphere. The resulting mixture was heated at 80° C. for 2 hours. The reaction mixture was quenched with H.sub.2O (800 mL) and extracted with EtOAc (2×600 mL). The combined organic layers were washed with brine (2×800 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 70:1 to 10:1) and then triturated with hexane (100 mL) to give the title compound (10.05 g, 72% yield, 96% purity on LCMS).

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

(49) LCMS: m/z 261.1 (M+H).sup.+ (ES.sup.+).

Step B: 4-(5-Fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine

(50) ##STR00039##

(51) To a solution of 4-fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl) aniline (1 g, 3.84 mmol, 1 eq) in THF (40 mL) was added TEA (777 mg, 7.68 mmol, 2 eq). Then triphosgene (456 mg, 1.54 mmol, 0.4 eq) was added in portions at 5° C. The mixture was stirred at 70° C. for 1 hour. The mixture was diluted with EtOAc (200 mL) and filtered through silica gel. The filtrate was concentrated in vacuo to give the title compound (1.1 g, crude) as a yellow oil, which was used directly in the next step.

Intermediate A4: 4-(4-Isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine

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

(52) ##STR00040##

(53) To a mixture of 2,3-dihydro-1H-indene (60 g, 507.72 mmol, 62.50 mL, 1 eq) in concentrated H.sub.2SO.sub.4 (30 mL) was added a mixture of HNO.sub.3 (50 mL, 69 wt % in water) and concentrated H.sub.2SO.sub.4 (50 mL) dropwise at 0° C. over a period of 3.5 hours. The reaction mixture was stirred at 0° C. for 0.5 hour. Then the reaction mixture was poured into ice water (600 mL) and extracted with ethyl acetate (2×400 mL). The combined organic layers were washed with water (500 mL), saturated aqueous NaHCO.sub.3 solution (500 mL) and brine (2×500 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 100:1) to give the title compound (55 g, 66%) as a colourless oil.

(54) .sup.1H NMR (CDCl.sub.3): δ 7.98 (d, 1H), 7.51 (d, 1H), 7.30 (t, 1H), 3.41 (t, 2H), 302 (t, 2H) and 2.22-2.20 (m, 2H).

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

(55) ##STR00041##

(56) To a solution of 4-nitro-2,3-dihydro-1H-indene (55 g, contained another regio-isomer) in MeOH (500 mL) was added Pd/C (5 g, 10 wt % loading on activated carbon) under N.sub.2 atmosphere. The suspension was degassed under vacuum and purged with H.sub.2 several times. The reaction mixture was stirred under H.sub.2 (50 psi) at 20° C. for 12 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 100:4) to give the title compound (19.82 g, 43% yield, 96.39% purity on LCMS) as a brown oil.

(57) .sup.1H NMR (CDCl.sub.3): δ 7.01 (t, 1H), 6.71 (d, 1H), 6.51 (d, 1H), 3.57 (br s, 2H), 2.93 (t, 2H), 2.75 (t, 2H) and 2.16-2.08 (m, 2H).

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

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

(59) ##STR00042##

(60) To a solution of 2,3-dihydro-1H-inden-4-amine (19.8 g, 148.66 mmol, 1 eq) and TEA (19.56 g, 193.26 mmol, 1.3 eq) in DCM (300 mL) was added dropwise Ac.sub.2O (17.45 g, 170.96 mmol, 1.15 eq) over 6 minutes at 0° C. Then the reaction mixture was warmed to 16° C. and stirred for 1.4 hours. The mixture was poured into water (500 mL) and extracted with DCM (2×300 mL). The combined organic phases were washed with brine (2×500 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (25.74 g, 96% yield, 96.69% purity on LCMS) as a white solid.

(61) .sup.1H NMR (CDCl.sub.3): δ 7.70 (d, 1H), 7.15 (t, 1H), 7.02 (d, 1H), 2.95 (t, 2H), 2.81 (t, 2H), 2.18 (s, 3H) and 2.15-2.08 (m, 2H).

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

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

(63) ##STR00043##

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

(65) .sup.1H NMR (CDCl.sub.3): δ 7.33 (d, 1H), 7.16 (s, 1H), 6.98 (d, 1H), 2.92-2.83 (m, 4H), 2.21 (s, 3H) and 2.10-2.02 (m, 2H).

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

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

(67) ##STR00044##

(68) A mixture of N-(5-bromo-2,3-dihydro-1H-inden-4-yl)acetamide (45.68 g, 179.76 mmol, 1 eq) in EtOH (200 mL) and concentrated HCl (300 mL, 36 wt % in water) was stirred at 80° C. for 36 hours. The reaction mixture was cooled to 0° C. in an ice bath and some solid precipitated. The suspension was filtered. The filter cake was washed with ice water (50 mL) and dried in vacuo to give the title compound (34.1 g, 72% yield, 94.08% purity on LCMS, HCl salt) as a grey solid.

(69) .sup.1H NMR (DMSO-d.sub.6): δ 7.67 (br s, 2H), 7.24 (d, 1H), 6.69 (d, 1H), 2.85 (t, 2H), 2.79 (t, 2H) and 2.04-1.96 (m, 2H).

(70) LCMS: m/z 212.0 (M+H).sup.+ (ES.sup.+).

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

(71) ##STR00045##

(72) A solution of (2-methoxypyridin-4-yl)boronic acid (25.11 g, 164.15 mmol, 1.2 eq), 5-bromo-2,3-dihydro-1H-inden-4-amine (34 g, 136.80 mmol, 1 eq, HCl salt) and K.sub.2CO.sub.3 (60.50 g, 437.74 mmol, 3.2 eq) in dioxane (500 mL) and H.sub.2O (100 mL) was degassed with nitrogen for 15 minutes before Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (6 g, 7.35 mmol, 0.053 eq) was added. The reaction mixture was heated to 80° C. for 12 hours. The mixture was poured into water (500 mL) and extracted with ethyl acetate (2×500 mL). The combined organic phases were washed with brine (2×700 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 10:1) to give the title compound (27.4 g, 79% yield, 95% purity on LCMS) as a white solid.

(73) .sup.1H NMR (CDCl.sub.3): δ 8.22 (d, 1H), 7.03-7.00 (m, 1H), 6.99 (d, 1H), 6.87 (s, 1H), 6.77 (d, 1H), 3.99 (s, 3H), 3.77 (br s, 2H), 2.97 (t, 2H), 2.77 (t, 2H) and 2.21-2.13 (m, 2H).

(74) LCMS: m/z 241.2 (M+H).sup.+ (ES.sup.+).

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

(75) ##STR00046##

(76) To a solution of 5-(2-methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (11 g, 45.78 mmol, 1 eq) and TEA (5.10 g, 50.35 mmol, 1.1 eq) in THF (275 mL) was added bis(trichloromethyl) carbonate (4.93 g, 16.61 mmol, 0.36 eq) in portions at 0° C. Then the reaction mixture was stirred at 16° C. for 0.5 hour. The reaction mixture was filtered and the filter cake was washed with THF (2 L). The filtrate was concentrated in vacuo to give the title compound (9.04 g, 74%) as a light yellow solid.

(77) .sup.1H NMR (CDCl.sub.3): δ 8.28 (d, 1H), 7.20-7.16 (m, 3H), 7.02 (s, 1H), 4.16 (s, 3H), 3.04-2.99 (m, 4H) and 2.23-2.15 (m, 2H).

Intermediate A.: 4-(7-Fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine

Step A: 7-Fluoro-4-nitro-2,3-dihydro-1H-inden-1-one

(78) ##STR00047##

(79) To a mixture of 7-fluoro-2,3-dihydro-1H-inden-1-one (9.5 g, 63.27 mmol, 1 eq) in concentrated H.sub.2SO.sub.4 (100 mL) was added dropwise a solution of HNO.sub.3 (5.37 mL, 82.25 mmol, 69 wt % in water, 1.3 eq) in concentrated H.sub.2SO.sub.4 (20 mL) at −15° C. Then the reaction mixture was stirred at 0° C. for 0.5 hour. The mixture was quenched with water (500 mL) at 0° C., and then extracted with EtOAc (3×300 mL). The combined organic phases were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 3:1) to give the title compound (11.4 g, 92%) as a yellow solid.

(80) .sup.1H NMR (CDCl.sub.3) δ 8.51 (dd, 1H), 7.22 (t, 1H), 3.69-3.65 (m, 2H) and 2.88-2.82 (m, 2H).

Step B: 7-Fluoro-4-nitro-2,3-dihydro-1H-inden-1-ol

(81) ##STR00048##

(82) To a mixture of 7-fluoro-4-nitro-2,3-dihydro-1H-inden-1-one (30 g, 153.73 mmol, 1 eq) in EtOH (450 mL) was added NaBH.sub.4 (11.63 g, 307.46 mmol, 2 eq) in portions. The reaction mixture was stirred at 15° C. for 1 hour. Then the mixture was poured into water (500 mL) and extracted with DCM (2×200 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (30 g, crude) as brown oil.

(83) .sup.1H NMR (CDCl.sub.3) δ 8.21 (dd, 1H), 7.08 (t, 1H), 5.59-5.56 (m, 1H), 3.66-3.59 (m, 1H), 3.44-3.39 (m, 1H), 2.56-2.51 (m, 1H) and 2.22-2.17 (m, 2H).

Step C: 4-Fluoro-7-nitro-2,3-dihydro-1H-indene

(84) ##STR00049##

(85) To a mixture of 7-fluoro-4-nitro-2,3-dihydro-1H-inden-1-ol (4.5 g, 22.82 mmol, 1 eq) in TFA (20 mL) was added Et.sub.3SiH (7.96 g, 68.47 mmol, 3 eq) in one portion. The reaction mixture was stirred at 25° C. for 12 hours. Then the mixture was quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated aqueous NaHCO.sub.3 solution (2×100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (5 g, crude) as brown oil.

(86) .sup.1H NMR (CDCl.sub.3) δ 8.06 (dd, 1H), 7.01 (t, 1H), 3.46 (t, 2H), 3.04 (t, 2H) and 2.25-2.20 (m, 2H).

Step D: 7-Fluoro-2,3-dihydro-1H-inden-4-amine

(87) ##STR00050##

(88) To a mixture of 4-fluoro-7-nitro-2,3-dihydro-1H-indene (5 g, 27.60 mmol, 1 eq) in MeOH (50 mL) was added Pd/C (0.5 g, 10 wt % loading on activated carbon) at 25° C. under a nitrogen atmosphere. Then the reaction mixture was stirred at 25° C. for 12 hours under hydrogen (15 psi). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 50:1 to 10:1) to give the title compound (1.8 g, 43%) as a brown solid.

(89) .sup.1H NMR (CDCl.sub.3) δ 6.69 (t, 1H), 6.44 (dd, 1H), 3.47 (br s, 2H), 2.95 (t, 2H), 2.75 (t, 2H) and 2.19-2.11 (m, 2H).

Step E: 5-Bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine

(90) ##STR00051##

(91) To a solution of 7-fluoro-2,3-dihydro-1H-inden-4-amine (8.3 g, 54.90 mmol, 1 eq) in toluene (100 mL) was added NBS (10.26 g, 57.65 mmol, 1.05 eq) in one portion at 25° C. The reaction mixture turned dark brown immediately and then the mixture was stirred at 25° C. for 30 minutes. The reaction mixture was quenched with saturated aqueous Na.sub.2SO.sub.3 solution (200 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 20:1) to give the title compound (8.51 g, 67%) as a brown solid.

(92) .sup.1H NMR (CDCl.sub.3) δ 6.99 (d, 1H), 3.81 (br s, 2H), 2.92 (t, 2H), 2.78 (t, 2H) and 2.21-2.13 (m, 2H).

Step F: 7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine

(93) ##STR00052##

(94) To a mixture of 5-bromo-7-fluoro-2,3-dihydro-1H-inden-4-amine (3.5 g, 15.21 mmol, 1 eq) and pyridin-4-ylboronic acid (1.96 g, 15.97 mmol, 1.05 eq) in dioxane (500 mL) and H.sub.2O (5 mL) was added K.sub.2CO.sub.3 (6.31 g, 45.64 mmol, 3 eq) and Pd(dppf)Cl.sub.2 (1.11 g, 1.52 mmol, 0.1 eq) in one portion under a nitrogen atmosphere. Then the reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was filtered. The filtrate was diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 10:1 to 2:1) to give the title compound (1.7 g, 45% yield, 90.98% purity on HPLC) as a brown solid.

(95) .sup.1H NMR (CDCl.sub.3) δ 8.68 (dd, 2H), 7.40 (dd, 2H), 6.72 (d, 1H), 3.76 (br s, 2H), 3.01 (t, 2H), 2.80 (t, 2H) and 2.26-2.18 (m, 2H).

Step G: 4-(7-Fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine

(96) ##STR00053##

(97) To a solution of 7-fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (400 mg, 1.75 mmol, 1 eq) and TEA (355 mg, 3.50 mmol, 2 eq) in THF (30 mL) was added bis(trichloromethyl) carbonate (208 mg, 700.94 μmol, 0.4 eq) at 0° C. The reaction mixture was stirred at 70° C. for 30 minutes. Then the reaction mixture was filtered through a pad of silica gel and the filter cake was washed with THF (20 mL). The filtrate was concentrated in vacuo to reduce to 10 mL, which was used directly in the next step.

Intermediate P1: (3,5-Dichlorophenyl)methanesulfonamide

(98) ##STR00054##

(99) To a solution of saturated ammonia in THF (5 mL) was added dropwise a solution of (3,5-dichlorophenyl)methanesulfonyl chloride (200 mg, 770.60 μmol, 1 eq) in THF (1 mL). The mixture was stirred at 20° C. for 1 hour and then concentrated under reduced pressure. The residue was diluted with water (5 mL) and then the mixture was extracted into ethyl acetate (2×5 mL). The combined organic layers were washed with brine (5 mL), dried (anhydrous Na.sub.2SO.sub.4), filtered and concentrated in vacuo to give the title compound (180 mg, 97%) as a white solid.

(100) .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.42 (d, 1H), 7.35 (d, 2H), 4.58 (br s, 2H) and 4.28 (s, 2H).

Intermediate P2: 2-Methylpropane-1-sulfonamide

(101) ##STR00055##

(102) A solution of 2-methylpropane-1-sulfonyl chloride (1.5 g, 9.58 mmol, 1 eq) in THF (20 mL) was cooled to 0° C. Then NH.sub.3 (15 psi) was bubbled into the mixture at 0° C. for 10 minutes. The mixture was stirred at 0° C. for another 10 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (1 g, 76%) as a colourless oil.

(103) .sup.1H NMR (DMSO-d.sub.6): δ 6.72 (s, 2H), 2.86 (d, 2H), 2.19-2.07 (m, 1H) and 1.01 (d, 6H).

Intermediate P3: 2-Phenylethanesulfonamide

(104) ##STR00056##

(105) NH.sub.3 was bubbled into THF (10 mL) at −78° C. for 5 minutes. Then a solution of 2-phenylethanesulfonyl chloride (0.5 g, 2.44 mmol, 1 eq) in THF (10 mL) was added to the NH.sub.3/THF solution at 25° C. The resulting mixture was stirred for 12 minutes. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (0.38 g, 84%) as a white solid.

(106) .sup.1H NMR (CDCl.sub.3): δ 7.38-7.33 (m, 2H), 7.29-7.24 (m, 3H), 4.42 (br s, 2H), 3.45-3.40 (m, 2H) and 3.22-3.17 (m, 2H).

(107) LCMS: m/z 208.1 (M+Na).sup.+ (ES.sup.+).

Intermediate P4: 1-Phenylethanesulfonamide

Step A: N,N-Bis(4-methoxybenzyl)-1-phenylmethanesulfonamide

(108) ##STR00057##

(109) To a solution of bis(4-methoxybenzyl)amine (4.05 g, 15.74 mmol, 1 eq) in DCM (40 mL) was added TEA (3.18 g, 31.47 mmol, 2 eq) and phenylmethanesulfonyl chloride (3 g, 15.74 mmol, 1 eq). The mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated in vacuo. The residue was treated with water (50 mL) and extracted with EtOAc (2×50 mL). The organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 5:1 to 3:1) to give the title compound (4 g, 62%) as a yellow solid.

(110) .sup.1H NMR (CDCl.sub.3): δ 7.24-7.20 (m, 3H), 7.11 (dd, 4H), 7.00-6.95 (m, 2H), 6.80 (dd, 4H), 4.03 (s, 2H), 3.96 (s, 4H) and 3.74 (s, 6H).

Step B: N,N-Bis(4-methoxybenzyl)-1-phenylethanesulfonamide

(111) ##STR00058##

(112) To a solution of N,N-bis(4-methoxybenzyl)-1-phenylmethanesulfonamide (1 g, 2.43 mmol, 1 eq) in THF (10 mL) was added LDA (2 M, 1.34 mL, 1.1 eq) at −78° C. under N.sub.2 atmosphere. The mixture was stirred at −78° C. for 1 hour. Iodomethane (379 mg, 2.67 mmol, 1.1 eq) was added and the resulting mixture was stirred at 20° C. for 2 hours. The reaction mixture was quenched with saturated aqueous NH.sub.4Cl solution (20 mL) and then concentrated in vacuo to remove THF. The mixture was treated with water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO.sub.2, petroleum ether:ethyl acetate, 1:0 to 5:1) to give the title compound (0.9 g, 87%) as a white solid.

(113) .sup.1H NMR (CDCl.sub.3): δ 7.33-7.28 (m, 3H), 7.14 (d, 4H), 7.10-7.08 (m, 2H), 6.86 (dd, 4H), 4.09 (d, 2H), 4.03-4.01 (m, 1H), 3.83 (s, 6H), 3.76 (d, 2H) and 1.79 (d, 3H).

Step C: 1-Phenylethanesulfonamide

(114) ##STR00059##

(115) To a solution of N,N-bis(4-methoxybenzyl)-1-phenylethanesulfonamide (900 mg, 2.11 mmol, 1 eq) in DCM (30 mL) was added TFA (46.20 g, 405.19 mmol, 191.58 eq). The mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated in vacuo. The residue was treated with MeOH (15 mL). The suspension was filtered and the filtrate was concentrated in vacuo. The residue was triturated with a mixture of petroleum ether and ethyl acetate (v:v=20:1, 10 mL) to give the title compound (300 mg, 77%) as a white solid.

(116) .sup.1H NMR (CDCl.sub.3): δ 7.47-7.39 (m, 5H), 4.46 (br s, 2H), 4.29 (q, 1H) and 1.82 (d, 3H).

(117) LCMS: m/z 208.1 (M+Na).sup.+ (ES.sup.+).

Intermediate P5: 3-Azidopropane-1-sulfonamide

(118) ##STR00060##

(119) To a solution of 3-chloropropane-1-sulfonamide (200 mg, 1.3 mmol) in acetone (10 mL) was added sodium azide (200 mg, 3 mmol) in water (1 mL). The mixture was refluxed for 36 hours. The solvents were evaporated. The residue was triturated with THF. The THF layer was filtered and evaporated to afford the title compound as a yellow oil (200 mg, 96%).

(120) .sup.1H NMR (CD.sub.3OD) δ 3.51 (t, 2H), 3.17 (t, 2H), 2.07 (m, 2H).

PREPARATION OF EXAMPLES

Example 1: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-phenyl Methanesulfonamide, Potassium Salt

(121) ##STR00061##

(122) To a cooled (o ° C.) solution of phenylmethanesulfonamide (40 mg, 0.23 mmol) in THF (2.5 mL) was added potassium tert-butoxide (26 mg, 0.23 mmol). The ice bath was removed and the reaction mixture was stirred whilst being allowed to warm to room temperature over 40 minutes. A solution of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1; 46 mg, 0.23 mmol) in THF (1 mL) was added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and DMSO (1 mL) was added. The suspension was filtered over cotton wool and subsequently submitted for purification by reversed phase column chromatography (see “Experimental Methods”) to afford the title compound (34 mg; 40%) as a white solid.

(123) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.43 (m, 2H), 7.28 (m, 3H), 6.86 (s, 1H), 4.45 (s, 2H), 2.82 (m, 8H) and 2.02 (m, 4H).

(124) LCMS: m/z 371 (M+H).sup.+ (ES.sup.+); 369 (M−H).sup.− (ES.sup.−).

Example 2: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-methylpropane-1-sulfonamide, Potassium Salt

(125) ##STR00062##

(126) Prepared as described for N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-phenyl methanesulfonamide, potassium salt (Example 1) using 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) and 2-methylpropane-1-sulfonamide (Intermediate P2) to afford the title compound (52%) as a white solid.

(127) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 6.86 (s, 1H), 3.11 (d, 2H), 2.82 (m, 8H), 2.22 (m, 1H), 2.02 (m, 4H) and 1.08 (d, 6H).

(128) LCMS: m/z 337 (M+H).sup.+ (ES.sup.+); 335 (M−H).sup.− (ES.sup.−).

Example 3: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide

(129) ##STR00063##

(130) Ethene sulfonamide (0.2 g, 1.3 mmol) was dissolved in THF (2.5 mL), the mixture cooled to 0° C. and potassium t-butoxide (0.21 g, 1.9 mmol) added. After stirring at 0° C. for 45 minutes 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (0.27 g, 1.4 mmol) in THF (2.5 mL) was added dropwise and the mixture stirred for 20 hours at room temperature. The resulting mixture was worked-up by evaporation in vacuo, taken up in DMSO (2-3 mL) and purified by column chromatography (RP-ISCO: 40 g RP-Silica column, eluent 0-70% methanol-water). The first and main fraction afforded the title compound (68 mg, 16%) after freeze-drying in 97% purity.

(131) HPLC-MS: 97% (ELSD), mass 306+1 (ACPI pos.).

(132) .sup.1H NMR (300 MHz, DMSO-d6) δ 7.31 (s, 1H), 6.86 (dd, J=16.9, 10.0 Hz, 1H), 6.77 (s, 1H), 5.71 (d, J=17.2 Hz, 1H), 5.40 (d, J=9.9 Hz, 1H), 2.73 (dt, J=17.8, 7.4 Hz, 9H), 1.92 (q, J=7.3 Hz, 4H).

Example 4: 1-(3,5-Dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, Sodium Salt

(133) ##STR00064##

(134) To a solution of (3,5-dichlorophenyl)methanesulfonamide (Intermediate Pt) (180 mg, 749.7 μmol) in THF (5 mL) was added sodium methoxide (40.5 mg, 749.7 μmol) at 20° C. After stirring for 15 minutes, 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (149.4 mg, 749.67 μmol) was added to the mixture. The mixture was stirred at 20° C. for 15 hours and then filtered. The collected solid was triturated with ethyl acetate (3×5 mL) and the combined layers were concentrated in vacuo to give the title compound (300 mg, 87%) as a white solid.

(135) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.45-7.44 (m, 1H), 7.32-7.28 (m, 3H), 6.79 (s, 1H), 4.28 (s, 2H), 2.77-2.73 (m, 8H) and 1.95-1.91 (m, 4H).

(136) LCMS: m/z 439 (M+H).sup.+ (ES.sup.+).

Example 5: 1-(4-Chlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, Sodium Salt

(137) ##STR00065##

(138) Prepared as described for 1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, sodium salt (Example 4) to afford the title compound (53 mg, 40%) as a white solid.

(139) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.30-7.29 (m, 4H), 7.21 (br s, 1H), 6.78 (s, 1H), 4.22 (s, 2H), 2.77-2.70 (m, 8H) and 1.95-1.92 (m, 4H).

(140) LCMS: m/z 405 (M+H).sup.+ (ES.sup.+).

Example 6: 1-(3,4-Dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, Sodium Salt

(141) ##STR00066##

(142) Prepared as described for 1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, sodium salt (Example 4) to afford the title compound (24 mg, 11%) as a white solid.

(143) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.52-7.50 (m, 2H), 7.28-7.23 (m, 2H), 6.78 (s, 1H), 4.26 (s, 2H), 2.77-2.72 (m, 8H) and 1.95-1.91 (m, 4H).

(144) LCMS: m/z 439 (M+H).sup.+ (ES.sup.+).

Example 7: 1-(4-Fluorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, Sodium Salt

(145) ##STR00067##

(146) Prepared as described for 1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, sodium salt (Example 4) to afford the title compound (125 mg, 61%) as a white solid.

(147) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.34-7.30 (m, 3H), 7.07 (t, 2H), 6.79 (s, 1H), 4.20 (s, 2H), 2.79-2.70 (m, 8H) and 1.95-1.91 (m, 4H).

(148) LCMS: m/z 389 (M+H).sup.+ (ES.sup.+).

Example 8: 1-(4-Cyanophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, Sodium Salt

(149) ##STR00068##

(150) Prepared as described for 1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, sodium salt (Example 4) to afford the title compound (99 mg, 40%) as a white solid.

(151) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.72 (d, 2H), 7.47 (d, 2H), 7.24 (br s, 1H), 6.78 (s, 1H), 4.34 (s, 2H), 2.77-2.69 (m, 8H) and 1.95-1.91 (m, 4H).

(152) LCMS: m/z 396 (M+H)+(ES.sup.+).

Example 9: Methyl 4-((N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamoyl)methyl)benzoate, Sodium Salt

(153) ##STR00069##

(154) Prepared as described for 1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, sodium salt (Example 4) to afford the title compound (125 mg, 72%) as a white solid.

(155) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.84 (d, 2H), 7.44 (d, 2H), 7.26 (br s, 1H), 6.79 (s, 1H), 4.32 (s, 2H), 3.84 (s, 3H), 2.79-2.70 (m, 8H) and 1.95-1.91 (m, 4H).

(156) LCMS: m/z 429 (M+H).sup.+ (ES.sup.+).

Example 10: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(4-(trifluoromethyl)phenyl)methanesulfonamide, Sodium Salt

(157) ##STR00070##

(158) Prepared as described for 1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, sodium salt (Example 4) to afford the title compound (102 mg, 29%) as a white solid.

(159) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.60 (d, 2H), 7.51 (d, 2H), 7.24 (br s, 1H), 6.78 (s, 1H), 4.33 (s, 2H), 2.77-2.70 (m, 8H) and 1.95-1.91 (m, 4H).

(160) LCMS: m/z 439 (M+H).sup.+ (ES.sup.+).

Example 11: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(3-methoxyphenyl)methanesulfonamide, Sodium Salt

(161) ##STR00071##

(162) Prepared as described for 1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, sodium salt (Example 4) to afford the title compound (172 mg, 31%) as a white solid.

(163) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.30-7.29 (m, 4H), 7.25 (br s, 1H), 6.78 (s, 1H), 4.21 (s, 2H), 3.33 (s, 3H), 2.77-2.72 (m, 8H) and 1.95-1.91 (m, 4H).

(164) LCMS: m/z 401 (M+H).sup.+ (ES.sup.+).

Example 12: 1-(4-Chloro-2-fluorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, Sodium Salt

(165) ##STR00072##

(166) Prepared as described for 1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, sodium salt (Example 4) to afford the title compound (198 mg, 67%) as a white solid.

(167) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.43-7.33 (m, 1H), 7.32-7.30 (m, 2H), 7.21-7.18 (m, 1H), 6.79 (s, 1H), 4.27 (s, 2H), 2.77-2.72 (m, 8H) and 1.95-1.91 (m, 4H).

(168) LCMS: m/z 423 (M+H).sup.+ (ES.sup.+).

Example 13: 1-(4-Chloro-3-fluorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, Sodium Salt

(169) ##STR00073##

(170) Prepared as described for 1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, sodium salt (Example 4) to afford the title compound (200 mg, 53%) as a white solid.

(171) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.48-7.44 (m, 1H), 7.31-7.27 (m, 2H), 7.16-7.14 (m, 1H), 6.79 (s, 1H), 4.25 (s, 2H), 2.78-2.69 (m, 8H) and 1.95-1.91 (m, 4H).

(172) LCMS: m/z 423 (M+H).sup.+ (ES.sup.+).

Example 14: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(p-tolyl)methanesulfonamide, Sodium Salt

(173) ##STR00074##

(174) Prepared as described for 1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, sodium salt (Example 4) to afford the title compound (234 mg, 60%) as a white solid.

(175) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.20-7.17 (m, 3H), 7.06-7.04 (m, 2H), 6.78 (s, 1H), 4.16 (s, 2H), 2.79-2.71 (m, 8H), 2.27 (S, 3H) and 1.95-1.92 (m, 4H).

(176) LCMS: m/z 385 (M+H).sup.+ (ES.sup.+).

Example 15: 1-(2-Chlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, Sodium Salt

(177) ##STR00075##

(178) Prepared as described for 1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, sodium salt (Example 4) to afford the title compound (36 mg, 34%) as a white solid.

(179) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.50-7.39 (m, 1H), 7.38-7.36 (m, 1H), 7.29, (br s, 1H), 7.25-7.22 (m, 2H), 6.78 (s, 1H), 4.43 (s, 2H), 2.77-2.73 (m, 8H) and 1.95-1.92 (m, 4H).

(180) LCMS: m/z 405 (M+H).sup.+ (ES.sup.+).

Example 16: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(2-(trifluoromethyl)phenyl)methanesulfonamide, Sodium Salt

(181) ##STR00076##

(182) Prepared as described for 1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, sodium salt (Example 4) to afford the title compound (21 mg, 15%) as a white solid.

(183) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.77 (d, 1H), 7.65 (d, 1H), 7.57-7.55 (m, 1H), 7.45-7.43 (m, 1H), 7.36 (m, 1H), 6.79 (s, 1H), 4.47 (s, 2H), 2.80-2.75 (m, 8H) and 1.95-1.92 (m, 4H).

(184) LCMS: m/z 439 (M+H).sup.+ (ES.sup.+).

Example 17: 1-(2-Bromophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, Sodium Salt

(185) ##STR00077##

(186) Prepared as described for 1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, sodium salt (Example 4) to afford the title compound (85 mg, 87%) as a white solid.

(187) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.57-7.53 (m, 2H), 7.37 (br s, 1H), 7.28-7.26 (m, 1H), 7.18-7.16 (m, 1H), 6.79 (s, 1H), 4.44 (s, 2H), 2.79-2.74 (m, 8H) and 1.98-1.90 (m, 4H).

(188) LCMS: m/z 451 (M+H).sup.+ (ES.sup.+).

Example 18: Methyl 2-((N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl) carbamoyl)sulfamoyl)methyl)benzoate

(189) ##STR00078##

(190) To a solution of methyl 2-(sulfamoylmethyl)benzoate (100 mg, 436.20 μmol) in THF (4 mL) was added sodium methoxide (23.56 mg, 436.20 μmol). The mixture was stirred at 20° C. for 30 minutes before 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (104.29 mg, 523.44 μmol, 1.2 eq) was added. The reaction mixture was stirred at 20° C. for 16 hours and then concentrated in vacuo. The crude product was purified by prep-HPLC (column: Phenomenex Gemini 150 mm*25 mm*10 μm; mobile phase: [water (0.04% NH.sub.3H.sub.2O+10 mM NH.sub.4HCO.sub.3)-acetonitrile]; B %: 20%-50%, 12 min) to give the title compound (46 mg, 25%) as a white solid.

(191) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.17 (br s, 1H), 7.88-7.86 (m, 2H), 7.63-7.61 (m, 1H), 7.57-7.55 (m, 1H), 7.42-7.40 (m, 1H), 6.98 (s, 1H), 5.19 (s, 2H), 3.79 (s, 3H), 2.85-2.81 (m, 4H), 2.74-2.72 (m, 4H) and 2.05-1.99 (m, 4H).

(192) LCMS: m/z 451 (M+Na).sup.+ (ES.sup.+).

Example 19: 1-(3-Bromophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, Sodium Salt

(193) ##STR00079##

(194) Prepared as described for 1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, sodium salt (Example 4) to afford the title compound (239 mg, 76%) as a white solid.

(195) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.49-7.48 (m, 1H), 7.43-7.41 (m, 1H), 7.31-7.29 (m, 2H), 7.25-7.21 (m, 1H), 6.79 (s, 1H), 4.25 (s, 2H), 2.80-2.74 (m, 8H) and 1.99-1.92 (m, 4H).

(196) LCMS: m/z 451 (M+H).sup.+ (ES.sup.+).

Example 20: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-(m-tolyl)methanesulfonamide, Sodium Salt

(197) ##STR00080##

(198) Prepared as described for 1-(3,5-dichlorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonamide, sodium salt (Example 4) to afford the title compound (323 mg, 96%) as a white solid.

(199) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.26 (s, 1H), 7.16-7.09 (m, 3H), 7.04-7.02 (m, 1H), 6.79 (s, 1H), 4.18 (s, 2H), 2.79-2.73 (m, 8H), 2.27 (s, 3H) and 1.97-1.90 (m, 4H).

(200) LCMS: m/z 407 (M+Na).sup.+ (ES.sup.+).

Example 21: 3-Azido-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl) propane-1-sulfonamide, Potassium Salt

(201) ##STR00081##

(202) To a solution of 3-azidopropane-1-sulfonamide (Intermediate P5) (200 mg, 2.1 mmol) in THF (15 mL) was added potassium tert-butoxide (236 mg, 2.1 mmol). The mixture was stirred at room temperature for 45 minutes. 4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (419 mg, 2.1 mmol) was added and the mixture was stirred for 2 hours at room temperature. Then the reaction mixture was concentrated in vacuo and a part of the mixture was dissolved in DMSO (1 mL) and submitted for purification by reversed phase column chromatography (see “Experimental Methods”, “Purification Method” to afford an initial amount of title compound (55 mg) as a white solid. The remainder of the batch was stored. LCMS: m/z 364 (M+H).sup.+ (ES.sup.+); 362 (M−H).sup.− (ES.sup.−).

Example 22: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-1-phenylmethanesulfonamide

(203) ##STR00082##

(204) To a solution of phenylmethanesulfonamide (61 mg, 355.51 μmol, 1 eq) in THF (2 mL) was added t-BuONa (34 mg, 355.51 μmol, 1 eq) and the mixture was stirred at 25° C. for 0.5 hour. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (intermediate A2) (0.1 g, 355.51 μmol, 1 eq) was added and the resulting mixture was heated to 70° C. and stirred for 0.1 hour. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 μm; mobile phase: [A: water (0.05% NH.sub.3.H.sub.2O); B: MeCN]; B %: 15%-45%, 11.5 min) to give the title compound (0.038 g, 23% yield, 99% purity on LCMS) as a white solid.

(205) .sup.1H NMR (DMSO-d.sub.6): δ 10.59 (br s, 1H), 8.77 (d, 1H), 8.12 (S, 1H), 7.80 (dd, 1H), 7.30-7.10 (m, 7H), 4.30 (s, 2H), 3.24-3.20 (m, 1H) and 1.20 (d, 6H).

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

Example 23: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-phenylmethanesulfonamide

(207) ##STR00083##

(208) To a solution of phenylmethanesulfonamide (60 mg, 349.28 μmol, 1 eq) in THF (2 mL) was added t-BuONa (34 mg, 349.28 μmol, 1 eq) and the mixture was stirred at 25° C. for 0.5 hour. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (intermediate A3) (0.1 g, 349.28 μmol, 1 eq) was added and the resulting mixture was heated to 70° C. and stirred for 0.1 hour. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 μm; mobile phase: [A: water (0.05% NH.sub.3.H.sub.2O); B: MeCN]; B %: 10%-40%, 11.5 min) to give the title compound (0.04 g, 25% yield, 99% purity on LCMS) as a white solid.

(209) .sup.1H NMR (DMSO-d.sub.6): δ 8.15 (d, 1H), 7.52 (br s, 1H), 7.34-7.11 (m, 6H), 7.10-6.95 (m, 2H), 6.87 (s, 1H), 4.27 (s, 2H), 3.85 (s, 3H), 3.25-3.19 (m, 1H) and 1.18 (d, 6H).

(210) LCMS: m/z 458.3 (M+H).sup.+ (ES.sup.+).

Example 24: N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-phenylmethanesulfonamide

(211) ##STR00084##

(212) To a solution of phenylmethanesulfonamide (64 mg, 375.52 μmol, 1 eq) in THF (2 mL) was added t-BuONa (36 mg, 375.52 μmol, 1 eq) and the mixture was stirred at 25° C. for 0.5 hour. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate A4) (0.1 g, 375.52 μmol, 1 eq) was added and the resulting mixture was heated to 70° C. and stirred for 0.1 hour. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 μm; mobile phase: [A: water (0.05% NH.sub.3.H.sub.2O); B: MeCN]; B %: 8%-38%, 11.5 min) to give the title compound (90.80 mg, 55% yield, 99% purity on LCMS) as a white solid.

(213) .sup.1H NMR (DMSO-d.sub.6): δ 8.14 (d, 1H), 7.50 (br s, 1H), 7.32-7.30 (m, 3H), 7.25-7.24 (m, 2H), 7.17 (d, 1H), 7.09 (d, 1H), 6.97 (dd, 1H), 6.80 (s, 1H), 4.37 (s, 2H), 3.87 (s, 3H), 2.94 (t, 2H), 2.85 (t, 2H) and 2.09-1.97 (m, 2H).

(214) LCMS: m/z 438.2 (M+H).sup.+ (ES.sup.+).

Example 25: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-phenylmethanesulfonamide

(215) ##STR00085##

(216) A mixture of phenylmethanesulfonamide (70 mg, 408.84 μmol, 1 eq) and t-BuONa (39 mg, 408.84 μmol, 1 eq) in THF (2 mL) was stirred at 25° C. for 10 minutes. Then 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (intermediate A5) (104 mg, 408.84 μmol, 1 eq) was added. The mixture was stirred at 70° C. for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Xtimate C18, 250 mm*50 mm*10 μm; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (16.61 mg, 10% yield, 100% purity on LCMS) as a white solid.

(217) .sup.1H NMR (DMSO-d.sub.6): δ 8.54 (d, 2H), 7.41 (d, 2H), 7.26-7.22 (m, 4H), 7.18-7.02 (m, 2H), 6.95 (d, 1H), 4.21 (s, 2H), 2.96 (t, 2H), 2.89 (t, 2H) and 2.12-2.03 (m, 2H).

(218) LCMS: m/z 426.2 (M+H).sup.+ (ES.sup.+).

Example 26: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-2-methylpropane-1-sulfonamide

(219) ##STR00086##

(220) To a solution of 2-methylpropane-1-sulfonamide (49 mg, 355.51 μmol, 1 eq) (intermediate P2) in THF (2 mL) were added t-BuONa (34 mg, 355.51 μmol, 1 eq) and 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (intermediate A2) (100 mg, 355.51 μmol, 1 eq). The reaction mixture was stirred at 20° C. for 20 minutes and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*5 μm, mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN], B %: 3%-33%, 12.0 min) to give the title compound (48.16 mg, 32%) as a white solid.

(221) .sup.1H NMR (DMSO-d.sub.6): δ 8.72 (d, 1H), 8.07 (s, 1H), 7.77 (s, 1H), 7.67 (s, 1H), 7.21 (d, 1H), 7.11 (d, 1H), 3.26-3.23 (m, 1H), 2.67-2.63 (m, 2H), 1.77-1.66 (m, 1H), 1.15 (d, 6H) and 0.84 (d, 6H).

(222) LCMS: m/z 419.2 (M+H).sup.+ (ES.sup.+).

Example 27: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-2-methylpropane-1-sulfonamide

(223) ##STR00087##

(224) To a solution of 2-methylpropane-1-sulfonamide (intermediate P2) (48 mg, 349.28 μmol, 1 eq) in THF (2 mL) were added t-BuONa (34 mg, 349.28 μmol, 1 eq) and 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (intermediate A3) (100 mg, 349.28 μmol, 1 eq). The reaction mixture was stirred at 25° C. for 10 minutes and then was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*5 μm, mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN], B %: 15%-45%, 11.5 min) to give the title compound (101.64 mg, 69% yield, 100% purity on LCMS) as a white solid.

(225) .sup.1H NMR (DMSO-d.sub.6): δ 8.17 (d, 1H), 7.91 (s, 1H), 7.27-7.24 (m, 1H), 7.06 (dd, 1H), 6.99 (d, 1H), 6.82 (s, 1H), 3.87 (s, 3H), 3.16-3.09 (m, 1H), 3.00 (d, 2H), 1.91-1.81 (m, 1H), 1.16 (d, 6H) and 0.91 (d, 6H).

(226) LCMS: m/z 424.2 (M+H).sup.+ (ES.sup.+).

Example 28: N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-2-methylpropane-1-sulfonamide

(227) ##STR00088##

(228) To a solution of 2-methylpropane-1-sulfonamide (intermediate P2) (55 mg, 401.36 μmol, 1 eq) in THF (2 mL) were added t-BuONa (39 mg, 401.36 μmol, 1 eq) and 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate A4) (167 mg, 401.36 μmol, 1 eq). The reaction mixture was stirred at 25° C. for 20 minutes and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 μm, mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN], B %: 18%-48%, 10 min) to give the title compound (16.29 mg, 10%) as a white solid.

(229) .sup.1H NMR (DMSO-d.sub.6): δ 8.15 (d, 1H), 7.93 (br s, 1H), 7.22 (d, 1H), 7.12 (d, 1H), 6.94-6.91 (m, 1H), 6.74 (s, 1H), 3.86 (s, 3H), 3.10 (d, 2H), 2.93 (t, 2H), 2.79 (t, 2H), 2.05-1.95 (m, 3H) and 0.95 (d, 6H).

(230) LCMS: m/z 404.2 (M+H).sup.+ (ES.sup.+).

Example 29: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-2-methylpropane-1-sulfonamide

(231) ##STR00089##

(232) To a solution of 2-methylpropane-1-sulfonamide (intermediate P2) (54 mg, 393.30 μmol, 1 eq) in THF (2 mL) was added t-BuONa (38 mg, 393.30 μmol, 1 eq). Then the mixture was stirred at 25° C. for 10 minutes. A solution of 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (intermediate A5) (100 mg, 393.30 μmol, 1 eq) in THF (2.5 mL) was added. The resulting mixture was stirred at 25° C. for 30 minutes and then concentrated in vacuo. The residue was purified by prep-HPLC (Column: Xtimate C18, 250 mm*50 mm*10 μm, mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN], B %: 1%-31%, 10.0 min) to give the title compound (45.33 mg, 29% yield, 100% purity on LCMS) as a white solid.

(233) .sup.1H NMR (DMSO-d.sub.6): δ 8.54 (d, 2H), 7.40 (d, 2H), 6.96 (d, 1H), 2.95 (t, 2H), 2.89-2.83 (m, 4H), 2.09-2.03 (m, 2H), 1.96-1.91 (m, 1H) and 0.93 (d, 6H).

(234) LCMS: m/z 392.2 (M+H).sup.+ (ES.sup.+).

Example 30: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-2-phenylethanesulfonamide

(235) ##STR00090##

(236) To a solution of 2-phenylethanesulfonamide (intermediate P3) (66 mg, 355.51 μmol, 1 eq) in THF (2 mL) was added t-BuONa (34 mg, 355.51 μmol, 1 eq) and the mixture was stirred at 25° C. for 0.5 hour. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (intermediate A2) (0.1 g, 355.51 μmol, 1 eq) was added and the resulting mixture was heated to 70° C. and stirred for 0.1 hour. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge C18, 150 mm*50 mm*10 μm; mobile phase: [A: water (0.05% NH.sub.3.H.sub.2O); B: MeCN]; B %: 12%-42%, 11.5 min) to give the title compound (0.07 g, 42% yield, 99% purity on LCMS) as a white solid.

(237) .sup.1H NMR (DMSO-d.sub.6): δ 10.77 (br s, 1H), 8.67 (d, 1H), 8.11 (s, 1H), 7.92 (br s, 1H), 7.80 (d, 1H), 7.31-7.18 (m, 5H), 7.09 (d, 2H), 3.25-3.19 (m, 3H), 2.70-2.51 (m, 2H) and 1.17 (d, 6H).

(238) LCMS: m/z 467.3 (M+H).sup.+ (ES.sup.+).

Example 31: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-2-phenylethanesulfonamide

(239) ##STR00091##

(240) To a solution of 2-phenylethanesulfonamide (intermediate P3) (65 mg, 349.28 μmol, 1 eq) in THF (2 mL) was added t-BuONa (34 mg, 349.28 μmol, 1 eq) and the mixture was stirred at 25° C. for 0.5 hour. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (intermediate A3) (0.1 g, 349.28 μmol, 1 eq) was added and the resulting mixture was heated to 70° C. and stirred for 0.1 hour. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 μm; mobile phase: [A: water (0.05% NH.sub.3.H.sub.2O); B: MeCN]; B %: 22%-52%, 11 min) to give the title compound (0.0317 g, 19% yield, 99% purity on LCMS) as a white solid.

(241) .sup.1H NMR (DMSO-d.sub.6): δ 8.10 (d, 1H), 8.00 (br s, 1H), 7.34-7.22 (m, 4H), 7.16-6.99 (m, 4H), 6.84 (s, 1H), 3.73 (s, 3H), 3.44-3.40 (m, 2H), 3.18-3.13 (m, 1H), 2.80-2.76 (m, 2H) and 1.16 (d, 6H).

(242) LCMS: m/z 472.2 (M+H).sup.+ (ES.sup.+).

Example 32: N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-2-phenylethanesulfonamide

(243) ##STR00092##

(244) To a solution of 2-phenylethanesulfonamide (intermediate P3) (70 mg, 375.52 μmol, 1 eq) in THF (2 mL) was added t-BuONa (36 mg, 375.52 μmol, 1 eq) and the mixture was stirred at 25° C. for 0.5 hour. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate A4) (0.1 g, 375.52 μmol, 1 eq) was added and the resulting mixture was heated to 70° C. and stirred for 0.1 hour. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 μm; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 17%-47%, 11 min) to give the title compound (0.021 g, 12% yield, 100% purity on LCMS) as a white solid.

(245) .sup.1H NMR (DMSO-d.sub.6): δ 8.07 (d, 1H), 7.50 (br s, 1H), 7.33-7.26 (m, 2H), 7.19-7.13 (m, 4H), 7.10-7.08 (m, 1H), 6.99 (d, 1H), 6.81 (s, 1H), 3.77 (s, 3H), 3.30-3.23 (m, 2H), 2.92 (t, 2H), 2.86-2.80 (m, 4H) and 2.07-1.98 (m, 2H).

(246) LCMS: m/z 452.2 (M+H).sup.+ (ES.sup.+).

Example 33: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-2-phenylethanesulfonamide

(247) ##STR00093##

(248) A mixture of 2-phenylethanesulfonamide (intermediate P3) (75 mg, 404.87 μmol, 1 eq) and t-BuONa (39 mg, 404.87 μmol, 1 eq) in THF (2 mL) was stirred at 25° C. for 10 minutes. Then 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (intermediate A5) (103 mg, 404.87 μmol, 1 eq) was added. The resulting mixture was stirred at 25° C. for 10 minutes, then warmed to 70° C. and stirred for 10 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Xtimate C18, 250 mm*50 mm*10 μm; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 10 min) to give the title compound (15.1 mg, 8% yield, 100% purity on LCMS) as a white solid.

(249) .sup.1H NMR (DMSO-d.sub.6): δ 8.53 (d, 2H), 7.63 (br s, 1H), 7.42 (d, 2H), 7.31 (t, 2H), 7.23-7.16 (m, 3H), 7.00 (d, 1H), 3.39-3.35 (m, 2H), 2.99 (t, 2H), 2.90-2.82 (m, 4H) and 2.10-2.06 (m, 2H).

(250) LCMS: m/z 440.2 (M+H).sup.+ (ES.sup.+).

Example 34: N-((2-(2-Cyanopyridin-4-yl)-4-fluoro-6-isopropylphenyl) carbamoyl)-1-phenylethanesulfonamide

(251) ##STR00094##

(252) To a solution of 1-phenylethanesulfonamide (intermediate P4) (50 mg, 269.92 μmol, 1 eq) in THF (2 mL) was added t-BuONa (26 mg, 269.92 μmol, 1 eq). After stirring at 20° C. for 10 minutes, 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)picolinonitrile (intermediate A2) (76 mg, 269.92 μmol, 1 eq) was added. The reaction mixture was stirred at 20° C. for 20 minutes and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini c18, 150 mm*25 mm*10 μm; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 22%-52%, 12 min) to give the title compound (14.74 mg, 11% yield, 98% purity on LCMS) as a white solid.

(253) .sup.1H NMR (DMSO-d.sub.6): δ 10.53 (br s, 1H), 8.77 (d, 1H), 8.10 (s, 1H), 7.97-7.93 (m, 1H), 7.77 (d, 1H), 7.32-7.24 (m, 4H), 7.23-7.19 (m, 3H), 4.57-4.54 (m, 1H), 3.15-3.12 (m, 1H), 1.46-1.40 (m, 3H) and 1.20-1.08 (m, 6H).

(254) LCMS: m/z 467.2 (M+H).sup.+ (ES.sup.+).

Example 35: N-((4-Fluoro-2-isopropyl-6-(2-methoxypyridin-4-yl)phenyl) carbamoyl)-1-phenylethanesulfonamide

(255) ##STR00095##

(256) To a solution of 1-phenylethanesulfonamide (intermediate P4) (50 mg, 269.92 μmol, 1 eq) in THF (2 mL) was added t-BuONa (26 mg, 269.92 μmol, 1 eq). The mixture was stirred at 20° C. for 10 minutes. Then 4-(5-fluoro-2-isocyanato-3-isopropylphenyl)-2-methoxypyridine (intermediate A3) (77 mg, 269.92 μmol, 1 eq) was added. The reaction mixture was stirred at 20° C. for 20 minutes and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Xtimate C18, 150 mm*25 mm*5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 10%-40%, 12 min) to give the title compound (12.98 mg, 10% yield, 100% purity on LCMS) as a white solid.

(257) .sup.1H NMR (DMSO-d.sub.6): δ 10.40 (br s, 1H), 8.15 (d, 1H), 7.70 (br s, 1H), 7.32-7.20 (m, 6H), 7.05-7.00 (m, 2H), 6.85 (s, 1H), 4.60-4.56 (m, 1H), 3.86 (s, 3H), 3.16-3.11 (m, 1H), 1.45 (d, 3H) and 1.18 (dd, 6H).

(258) LCMS: m/z 472.2 (M+H).sup.+ (ES.sup.+).

Example 36: N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-phenylethanesulfonamide

(259) ##STR00096##

(260) To a solution of 1-phenylethanesulfonamide (intermediate P4) (50 mg, 269.92 μmol, 1 eq) in THF (2 mL) was added t-BuONa (26 mg, 269.92 μmol, 1 eq). The mixture was stirred at 20° C. for 10 minutes. Then 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (intermediate A4) (72 mg, 269.92 μmol, 1 eq) was added and then the resulting mixture was stirred at 20° C. for 20 minutes. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Xtimate C18, 150 mm*25 mm*5 μm; mobile phase: [A: water (0.05% ammonium hydroxide v/v); B: MeCN]; B %: 5%-35%, 12 min) to give the title compound (34.56 mg, 28% yield, 99.8% purity on LCMS) as a white solid.

(261) .sup.1H NMR (DMSO-d.sub.6): δ 8.12 (d, 1H), 7.60 (br s, 1H), 7.33-7.30 (m, 5H), 7.19 (d, 1H), 7.09 (d, 1H), 6.94-6.92 (m, 1H), 6.77 (s, 1H), 4.69-4.66 (m, 1H), 3.86 (s, 3H), 2.93 (t, 2H), 2.81 (t, 2H), 2.07-2.01 (m, 2H) and 1.54 (d, 3H).

(262) LCMS: m/z 452.2 (M+H).sup.+ (ES.sup.+).

Example 37: N-((7-Fluoro-5-(pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)-1-phenylethanesulfonamide

(263) ##STR00097##

(264) To a solution of 1-phenylethanesulfonamide (intermediate P4) (75 mg, 404.87 μmol, 1 eq) in THF (2 mL) was added t-BuONa (39 mg, 404.87 μmol, 1 eq). Then the reaction mixture was stirred at 20° C. for 10 minutes. A solution of 4-(7-fluoro-4-isocyanato-2,3-dihydro-1H-inden-5-yl)pyridine (intermediate A5) (103 mg, 404.87 μmol, 1 eq) in THF (2 mL) was added. The resulting mixture was stirred at 20° C. for 20 minutes and then concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18, 150 mm*25 mm*10 μm; mobile phase: [A: water (10 mM NH.sub.4HCO.sub.3); B: MeCN]; B %: 13%-43%, 10 min) to give the title compound (63.22 mg, 35% yield, 99% purity on LCMS) as a light red solid.

(265) .sup.1H NMR (DMSO-d.sub.6): δ 8.57 (d, 2H), 7.69 (br s, 1H), 7.37-7.30 (m, 7H), 7.02 (d, 1H), 4.75-4.67 (m, 1H), 2.98 (t, 2H), 2.84 (t, 2H), 2.14-2.08 (m, 2H) and 1.55 (d, 3H).

(266) LCMS: m/z 440.2 (M+H).sup.+ (ES.sup.+).

Example 38: N-((5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)methanesulfonamide

(267) ##STR00098##

(268) 5-(2-Methoxypyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (326 mg, 1.36 mmol) (Intermediate A4, step F) was dissolved in THF (5 mL). Triethylamine (208 μl, 1.49 mmol) was added, followed by a solution of bis(trichloromethyl) carbonate (382 mg, 1.29 mmol) in THF (2 mL). The thick reaction mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the solid formed was dried under high vacuum for 1 hour. The solid, 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine, was suspended in THF (8 mL) of which 2 mL were used later. Methanesulfonamide (30 mg, 0.315 mmol) was suspended in THF (2 mL), sodium tert-butoxide (2 M in THF) (175 μl, 0.351 mmol) was added, and the mixture was stirred for 30 minutes at room temperature. Then a solution of 4-(4-isocyanato-2,3-dihydro-1H-inden-5-yl)-2-methoxypyridine (78 mg, 0.292 mmol) in THF (2 mL), prepared earlier, was added and the mixture was stirred overnight at room temperature. The THF was removed in vacuo and the residue was dissolved in DMSO (2 mL) and then purified by basic prep HPLC to afford the title compound (23.5 mg, 21%) as a colourless solid.

(269) .sup.1H NMR (DMSO-d.sub.6): δ 8.17 (d, J=5.3 Hz, 1H), 7.86 (s, 1H), 7.22 (d, J=7.9 Hz, 1H), 7.14 (d, J=7.7 Hz, 1H), 6.95 (dd, J=5.3, 1.3 Hz, 1H), 6.77 (s, 1H), 3.88 (s, 3H), 3.01 (s, 3H), 2.94 (t, J=7.4 Hz, 2H), 2.82 (t, J=7.4 Hz, 2H), 2.04 (p, J=7.5 Hz, 2H). NH not observed.

(270) LCMS; m/z 362.2 (M+H).sup.+ (ES.sup.+); 360.0 (M−H).sup.− (ES.sup.−).

Example 39: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-1-phenylethanesulfonamide

(271) ##STR00099##

(272) NaO.sup.tBu (2 M in THF, 0.16 mL, 0.32 mmol) was added to a solution of 1-phenylethanesulfonamide (Intermediate P4) (60 mg, 0.308 mmol) in THF (3.5 mL) at room temperature. The mixture was stirred for 1 hour, before 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) (0.067 g, 0.338 mmol) was added in a single portion and the reaction mixture was stirred for 21 hours at room temperature. EtOAc (10 mL) was added, followed by aq 2 M NaOH (˜0.2 mL) and water (3 mL). The phases were separated and the organic phase was extracted with water (3 mL). The combined aqueous phases were filtered and purified by chromatography on RP Flash C18 (12 g column, 0-100% MeCN/10 mM ammonium bicarbonate) to afford the title compound (15 mg, 13%) as a white solid.

(273) LCMS; m/z 385.3 (M+H).sup.+ (ES.sup.+).

(274) .sup.1H NMR (DMSO-d6) δ 10.10 (s, 1H), 7.87 (s, 1H), 7.40 (m, 5H), 6.97 (s, 1H), 4.88 (q, J=7.1 Hz, 1H), 2.82 (t, J=7.4 Hz, 4H), 2.69 (t, J=7.4 Hz, 4H), 2.00 (p, J=7.4 Hz, 4H), 1.69 (d, J=7.2 Hz, 3H).

Example 40: N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-phenylethanesulfonamide

(275) ##STR00100##

(276) Prepared according to the general procedure of N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-phenylethanesulfonamide (Example 39) from 2-phenylethanesulfonamide (Intermediate P3) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (Intermediate A1) to afford the title compound (35 mg, 37%) as a colourless solid.

(277) .sup.1H NMR (DMSO-d6) δ 10.35 (s, 1H), 8.18 (s, 1H), 7.37-7.29 (m, 2H), 7.29-7.21 (m, 3H), 6.97 (s, 1H), 3.77-3.65 (m, 2H), 3.09-2.97 (m, 2H), 2.82 (t, J=7.4 Hz, 4H), 2.70 (t, J=7.4 Hz, 4H), 2.03-1.93 (m, 4H).

(278) LCMS; m/z 385.4 (M+H).sup.+ (ES.sup.+).

Examples—Biological Studies

(279) NLRP3 and Pyroptosis

(280) 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-1β) from the cell.

(281) THP-1 Cells: Culture and Preparation

(282) THP-1 cells (ATCC #TIB-202) were grown in RPMI containing L-glutamine (Gibco #11835) supplemented with ImM 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.δ cells/ml). On the day of the experiment, THP-1 cells were harvested and resuspended into RPMI medium (without FBS). The cells were then counted and viability (>90%) checked by Trypan blue (Sigma #T8154). Appropriate dilutions were made to give a concentration of 625,000 cells/ml. To this diluted cell solution was added LPS (Sigma #L4524) to give a 1 μg/ml Final Assay Concentration (FAC). 40l of the final preparation was aliquoted into each well of a 96-well plate. The plate thus prepared was used for compound screening.

(283) THP-1 Cells Pyroptosis Assay

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

(285) 96-Well Plate Map

(286) TABLE-US-00005 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

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

(288) Human Whole Blood IL113 Release Assay

(289) For systemic delivery, the ability to inhibit NLRP3 when the compounds are present within the bloodstream is of great importance. For this reason, the NLRP3 inhibitory activity of a number of compounds in human whole blood was investigated in accordance with the following protocol.

(290) Human whole blood in Li-heparin tubes was obtained from healthy donors from a volunteer donor panel. 1. Plate out 80 μl of whole blood containing 1 μg/ml of LPS in 96-well, clear bottom cell culture plate (Corning #3585) 2. Add 10 μl compound (8 points half-log dilution with 10 μM top dose) or vehicle (DMSO 0.1% FAC) to the appropriate wells 3. Incubate for 3 hrs at 37° C., 5% CO.sub.2 4. Add 10 μl nigericin (Sigma #N7143) (10 μM FAC) to all wells 5. Incubate for 1 hr at 37° C., 5% CO.sub.2 6. At the end of the incubation period, spin plates at 300×g for 5 mins to pellet cells and remove 20 μl of supernatant and add to 96-well v-bottom plates for IL-1β analysis (note: these plates containing the supernatants can be stored at −80° C. to be analysed at a later date) 7. IL-1β was measured according to the manufacturer protocol (Perkin Elmer-AlphaLisa IL-1 Kit AL220F-5000) 8. IC.sub.50 data is fitted to a non-linear regression equation (log inhibitor vs response-variable slope 4-parameters)

(291) The results of the human whole blood assay are summarised in Table 1 below as HWB IC.sub.50.

(292) TABLE-US-00006 TABLE 1 NLRP3 inhibitory activity in THP-1 Cells (≤10 μM = ‘+’, ≤2.0 μM = ‘++’, ≤1.5 μM = ‘+++’, ≤1.0 μM = ‘++++’, not determined = ‘ND’). NLRP3 inhibitory activity in HWB (>10 μM = ‘.circle-solid.’, ≤10 μM = ‘.circle-solid..circle-solid.’, ≤7.5 μM = ‘.circle-solid..circle-solid..circle-solid.’, ≤5.0 μM = ‘.circle-solid..circle-solid..circle-solid..circle-solid.’, ND = not determined). Example No THP IC.sub.50 HWB IC.sub.50 1 ++++ .circle-solid..circle-solid..circle-solid..circle-solid. 2 ++++ ND 3 ++++ .circle-solid..circle-solid..circle-solid..circle-solid. 4 ++++ .circle-solid. 5 ++++ .circle-solid..circle-solid..circle-solid. 6 ++++ .circle-solid. 7 ++++ .circle-solid..circle-solid..circle-solid..circle-solid. 8 ++++ .circle-solid..circle-solid..circle-solid..circle-solid. 9 ++++ .circle-solid..circle-solid..circle-solid..circle-solid. 10 ++++ .circle-solid..circle-solid..circle-solid. 11 ++++ .circle-solid..circle-solid. 12 ++++ .circle-solid. 13 ++++ .circle-solid. 14 ++++ .circle-solid..circle-solid..circle-solid. 15 ++++ .circle-solid. 16 ++++ ND 17 ++++ ND 18 ++++ ND 19 ++++ .circle-solid. 20 ++++ .circle-solid..circle-solid..circle-solid. 21 ++++ .circle-solid..circle-solid..circle-solid..circle-solid. 22 + ND 23 ++++ ND 24 ++ ND 25 + ND 26 + ND 27 ++++ ND 28 ++++ ND 29 ++++ ND 30 ++++ ND 31 ++++ ND 32 ++++ ND 33 ++++ .circle-solid..circle-solid..circle-solid. 34 + ND 35 ++ ND 36 ++++ ND 37 ++ ND 38 ++++ ND 39 ++++ .circle-solid..circle-solid. 40 ++++ .circle-solid.

(293) As is evident from the results presented in Table 1, surprisingly in spite of the structural differences versus the prior art compounds, the compounds of the invention show high levels of NLRP3 inhibitory activity. In particular, it is evident from the data that the compounds of the invention are particularly suited to topical routes of administration.

(294) 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.