Human helicase DDX3 inhibitors as therapeutic agents

10941121 · 2021-03-09

Assignee

AZIENDA OSPEDALIERA UNIVERSITARIA SENESE (Siena, IT)

Inventors

Cpc classification

International classification

Abstract

The present invention refers to compounds endowed with RNA helicase DDX3 inhibitory activity of formula I and II and their therapeutic use, in particular for the treatment of viral diseases.

Claims

1. A compound selected from the group consisting of: ##STR00205## ##STR00206## ##STR00207## ##STR00208## ##STR00209## ##STR00210## ##STR00211## ##STR00212## ##STR00213## ##STR00214## ##STR00215## ##STR00216## ##STR00217## ##STR00218## or salt, solvate, stereoisomer thereof.

2. A compound according to claim 1 selected from the group consisting of: ##STR00219## ##STR00220## ##STR00221## or pharmaceutical acceptable salt, solvate, stereoisomer thereof.

3. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable excipient.

4. The pharmaceutical composition according to claim 3 further comprising at least one antiviral agent.

5. The pharmaceutical composition according to claim 4 wherein the antiviral agent is selected from the group consisting of: a nucleoside or a non-nucleoside analogue reverse-transcriptase inhibitor, a nucleotide analogue reverse-transcriptase inhibitor, a NS3/4A serine protease inhibitor, a NS5B polymerase inhibitor and interferon alpha.

6. A method for treating a viral disease comprising administering to a patient a compound or pharmaceutical acceptable salt, solvate, or stereoisomer of claim 1 to a patient in need thereof.

7. The method according to claim 6 wherein the viral disease is modulated by DDX3.

8. The method according to claim 6 wherein the viral disease is caused by a virus that is resistant to at least one compound selected from the group consisting of: protease inhibitor, nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor and integrase inhibitor.

9. The method according to claim 6 wherein the viral disease is caused by a virus selected from the group consisting of: Human Immunodeficiency Virus 1 (HIV-1), Hepatitis C Virus, Hepatitis B Virus, Eastern Equine Encephalitis Virus, Western Equine Encephalitis Virus, Venezuelan Equine Encephalitis Virus, Japanese Encephalitis Virus, Tick Borne Encephalitis Virus, Yellow Fever Virus, St. Louis Encephalitis Virus, Murray Valley Encephalitis Virus, Powassan Virus, Dengue Virus, Zika Virus, West Nile Virus, Rubella Virus, Cytomegalovirus, O'nyong'nyong Virus, Mayaro Virus, Ross River Virus, Sindbis Virus, Vaccinia Virus, Influenza Virus, Norovirus, SARS Coronavirus, Chikunguya Virus, Lassa Virus, Ebola Virus, Lujo Virus, Pneumovirus, Severe Fever With Thrombocytopenia Syndrome Virus, Porcine Reproductive And Respiratory Syndrome Virus, Poxvirus, Bovine Viral Diarrhea Virus (BVDV), Border Disease Virus (BDV) of sheep, and Classical Swine Fever Virus (CSFV).

10. The method of claim 9 wherein the virus is selected from the group consisting of: Human Immunodeficiency Virus 1 (HIV-1), Hepatitis C Virus, West Nile Virus, Dengue Virus, Japanese Encephalitis Virus, Porcine Reproductive And Respiratory Syndrome Virus, Ebola Virus, and Zika Virus.

11. The method of claim 10 wherein the virus is selected from the group consisting of: Ebola Virus and Zika Virus.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) Material and Methods

(2) Synthesis

(3) General

(4) Reagents were obtained from commercial suppliers (for example Sigma-Aldrich). All commercially available chemicals were used as purchased without further purification. CH.sub.3CN was dried over calcium hydride, CH.sub.2Cl.sub.2 was dried over calcium hydride and THF was dried over Na/benzophenone prior to use while DMF was bought already anhydrous. Anhydrous reactions were run under a positive pressure of dry N.sub.2 or argon. TLC was carried out using Merck TLC plates silica gel 60 F254. Chromatographic purifications were performed on columns packed with Merk 60 silica gel, 23-400 mesh, for flash technique. .sup.1H-NMR and .sup.13C-NMR spectra were recorded at 400 MHz on a Brucker Avance DPX400 spectrometer. Chemical shifts are reported relative to tetramethylsilane at 0.00 ppm. .sup.1H patterns are described using the following abbreviations: s=singlet, d=doublet, t=triplet, q=quartet, quint=quintet, sx=sextet, sept=septet, m=multiplet, br=broad signal, br s=broad singlet.

(5) Mass spectra (MS) data were obtained using an Agilent 1100 LC/MSD VL system (G1946C) with a 0.4 mL/min flow rate using a binary solvent system 25 of 95:5 methyl alcohol/water. UV detection was monitored at 254 nm. Mass spectra were acquired in positive and negative mode scanning over the mass range.

(6) Microwave Irradiation Experiments

(7) Microwave irradiation experiments were conducted using CEM Discover Synthesis Unit (CEM Corp., Matthews, N.C.). The machine consists of a continuous focused microwave power delivery system with operator selectable power output from 0 to 300 W. The temperature of the contents vessels was monitored using calibrated infrared temperature control mounted under the reaction vessel. All the experiments were performed using a stirring option whereby the contents of the vessels are stirred by means of rotating magnetic plate located below the floor of the microwave cavity and a Teflon-coated magnetic stir bar in the vessel.

(8) In the present invention the following abbreviations are used:

(9) TABLE-US-00001 NMR (Nuclear Magnetic Resonance) .sup.1H (proton) MHz (Megahertz) .sup.13C (carbon) .sup.19F (fluorine) LC-MS (Liquid Chromatography Mass Spectrum) Hz (Hertz) HPLC (High Performance Liquid Chromatography) s (seconds) min (minutes) h (hour(s)) mg (milligrams) g (grams) l (microlitres) mL (millilitres) mmol (millimoles) nm (nanometers) M (micromolar) M (molarity) SI selectity index DMEM (Dulbecco's Modified o.n. (overnight) Eagle's Medium) BOC or boc (tert-butyloxycarbonyl) DMF (dimethylformamide) DCM (dichloromethane) ACN (acetonitrile) Pyr Pyridine RT or rt or r.t. (room temperature) DMF (dimethylformamide) DMSO (dimethyl sulfoxide) DMSO d-.sub.6 (deuterated dimethyl sulfoxide) MeOH (methanol) MeOD-d.sub.4 (deuterated methanol) CDCl.sub.3-d (deuterated chloroform) Et.sub.2O (diethyl ether) EtOAc or EA (ethyl acetate) EtOH (ethanol) AcOH (acetic acid) iPrOH (isopropanol) D.sub.2O (deuterated water) TEA (triethylamine) THF (tetrahydrofuran) TMSN.sub.3 (Trimethylsilyl Azide) t-BuONO (tert-Butyl nitrite) PE (petroleum ether) t-Bu (tert-butyl) t.sub.R (retention time) Cmpd. (compound) wt wild type MTBE (methyl tert-butyl ether)

(10) Except where indicated otherwise, all temperatures are expressed in C. (degrees centigrade) or K (Kelvin).

(11) The yields were calculated assuming that products were 100% pure if not stated otherwise.

EXAMPLES

Example 1

(12) ##STR00053##

(13) General Procedure for the Synthesis of Compounds 3a and 3b:

(14) The opportune aniline 2 or 72 (3.62 mmol) was added to a solution of the opportune isocyanate 1 or 1a (5.43 mmol) in anhydrous CH.sub.2Cl.sub.2 (10 mL) in one portion. The solution was stirred for 4 hours at 60 C. under a nitrogen atmosphere. The yellow precipitate was filtered, washed with cool DCM and petroleum ether and dried under high vacuum to afford the desired product as a white solid.

(15) 1-(4-nitrophenyl)-3-o-tolylurea (3a). Yield=63%; .sup.1H NMR (400 MHz, DMSO d-.sub.6): 9.7 (s, 1H, NH), 8.19-8.16 (d, J=9.2 Hz, 2H), 8.13 (s, 1H), 7.78-7.76 (d, J=8.0 Hz, 1H), 7.69-7.66 (d, J=12.0 Hz, 2H), 7.19-7.13 (m, 2H), 7.00-6.97 (t, 1H, J=12.0 Hz), 2.24 (s, 3H) ppm. MS (ESI) m/z 270 [MH].sup., 306 [M+Cl].sup..

(16) 1-(2-methoxy-4-nitrophenyl)-3-(2-(trifluoromethyl)phenyl)urea (3b): Yield=56%; .sup.1H NMR (400 MHz, MeOD): 8.40-8.38 (d, J=8.8 Hz, 1H), 7.95-7.91 (m, 2H), 7.74-7.73 (d, J=2.0 Hz, 1H), 7.66-7.64 (d, J=8.0 Hz, 1H), 7.61-7.57 (t, J=7.8 Hz, 1H), 7.45 (s, 1H), 3.97 (s, 3H) ppm. MS (ESI) m/z 354 [MH].sup..

(17) General Procedure for the Synthesis of 4a and 4b:

(18) The opportune Urea 3a or 3b (1.10 mmol) was solubilized in 30 mL of anhydrous MeOH, and Palladium on charcoal (50 mg) was added. The reaction mixture was stirred under Hydrogen atmosphere for 1 h, then the mixture was filtered off on a celite pad, the solvent evaporated at reduced pressure and the residue crystallized from acetonitrile.

(19) 1-(4-aminophenyl)-3-o-tolylurea (4a). Yield=70%; white solid. .sup.1H NMR (400 MHz, DMSO d-.sub.6): 8.48 (s, 1H), 7.83-7.81 (d, J=8.0 Hz, 2H), 7.67 (s, 1H), 7.15-7.05 (m, 4H), 6.89-6.87 (d J=8.0 Hz, 1H), 6.50-6.48 (d, J=8.0 Hz, 2H), 4.72 (s, 2H), 2.20, (s, 3H) ppm. MS (ESI) m/z 242.0 [M+H]+, 264 [M+Na].sup.+, 505 [2M+Na].sup.+.

(20) 1-(4-amino-2-methoxyphenyl)-3-(2-(trifluoromethyl)phenyl)urea (4b): Yield=70%; white solid. .sup.1H NMR (400 MHz, MeOD): 8.04-8.02 (d, J=8.0 Hz, 1H), 7.49-7.44 (m, 2H), 7.38-7.36 (d, J=8.0 Hz, 1H), 7.10-7.06 (t, J=7.6 Hz, 1H), 6.27-6.26 (d, J=6.0 Hz, 2H), 3.74 (s, 3H) ppm. MS (ESI) m/z 326 [M+H].sup.+.

(21) General Procedure for the Synthesis of 5a and 5b:

(22) The opportune Aniline 4a or 4b (0.41 mmol) was dissolved in CH.sub.3CN and cooled to 0 C. in an ice-salt bath. To this stirred solution, was added tBuONO (0.61 mmol), and the mixture was stirred for 10 min, after this time, TMSN.sub.3 (65 L, 0.49 mmol) was added dropwise, during 10 minutes, and the resulting brown solution was stirred at r.t. One hour later the solvent was removed at reduced pressure and the residue was purified by flash chromatography on silica gel 1-(4-azidophenyl)-3-o-tolylurea (5a). (Purification Eluent: DCM-MeOH 9:1). Yield 67%. .sup.1H NMR (400 MHz, CDCl.sub.3-d) 9.10 (s, 1H), 7.91 (s, 1H), 7.80-7.78 (d, J=8.0 Hz, 1H), 7.50-7.48 (d, J=8.0 Hz, 2H), 7.16-7.19 (m, 2H), 7.04-7.02 (d, J=8.0 Hz, 2H), 7.95-7.91 (t, J=8.0 Hz, 1H), 2.22 (s, 3H) ppm. MS (ESI) m/z 267 [M+Na].sup.+, 557 [2M+Na].sup.+.

(23) 1-(4-azido-2-methoxyphenyl)-3-(2-(trifluoromethyl)phenyl)urea (5b): (Purification Eluent: PE-EA=5:3). Yield=98%; yellow solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.41 (s, 1H), 8.23-8.18 (t, J=9.0 Hz, 1H), 8.06-8.00 (m, 2H), 7.62-7.55 (m, 2H), 7.24-7.20 (t, J=7.6 Hz, 1H), 3.84 (s, 3H) ppm.

(24) General Procedure for the Preparation of Compounds 8 a-e

(25) The appropriate alkyne (0.10 mmol) and azide 5 (25 mg, 0.09 mmol) were suspended in a 1:1 mixture of water and t-BuOH (1.5 mL each) in a 10 mL glass vial equipped with a small magnetic stirring bar. To this, was added sodium ascorbate (0.1 equiv) and copper(II) sulfate pentahydrate (0.10 mmol). The mixture was then heated for 10 min. at 125 C. under microwave irradiation, using an irradiation power of 300 W. After this time the precipitate was filtered-off and purified on silica, to give final products 8a, 8b, 8c, 8d or 8e.

(26) 1-(4-(4-phenyl-1H-1,2,3-triazol-1-yl)phenyl)-3-o-tolylurea (8a). The residue was purified by flash chromatography on silica gel (DCM/MeOH 98:2). Yield 97%, white solid. .sup.1H NMR (400 MHz, DMSO d-.sub.6): 9.42 (s, 1H), 9.18 (s, 1H), 8.08 (s, 1H), 7.93-7.91 (d, J=8.0 Hz, 2H), 7-85-7-80 (m, 3H), 7.70-7.68 (d, J=8.0 Hz, 2H), 7.50-7.46 (m, 3H), 7.38-7.34 (t, J=8.0 Hz, 1H), 7.18-7.14 (m, 2H), 6.97-6.94 (t, J=12.0 Hz, 1H), 2.25 (s, 3H) ppm. .sup.13C-NMR (100 MHz, DMSO d-.sub.6): 153.09, 148.24, 140.57, 137.65, 131.33, 130.87, 130.71, 129.45, 128.63, 126.66, 125.79, 123.48, 121.83, 121.35, 119.88, 119.12 ppm. MS (ESI) m/z 368 [MH].sup., 404 [M+Cl].sup..

(27) 1-(4-(4-tert-butyl-1H-1,2,3-triazol-1-yl)phenyl)-3-o-tolylurea (8b). The residue was purified by flash chromatography on silica gel (DCM/MeOH 98:2). Yield 91%, white solid. .sup.1H NMR (400 MHz, DMSO d-.sub.6): 9.23 (s, 1H), 8.45 (s, 1H), 7.96 (s, 1H), 7.80-7.75 (m, 3H, Ph), 7.63-7.61 (d, J=8.0 Hz, 2H), 7.17-7.11 (m, 2H), 6.96-6.93 (t, J=12.0 Hz, 1H), 2.23 (s, 3H), 1.32 (s, 9H) ppm. .sup.13C-NMR (100 MHz, DMSO d-.sub.6): 158.38, 155.30, 139.59, 135.73, 131.87, 131.75, 130.66, 126.64, 125.48, 124.84, 121.22, 120.18, 117, 50, 30.33, 17.83 ppm. MS (ESI) m/z 348 [MH].sup., 384 [M+Cl].sup..

(28) 1-(4-(4-methanamine,N-[(phenyl)methyl]-N-methyl-1H-1,2,3-triazol-1yl)phenyl)-3-o-tolylurea (8c). The residue was purified by flash chromatography on silica gel (DCM/MeOH 98:2). Yield 90%, white solid. .sup.1H NMR (400 MHz CDCl.sub.3-d): 8.43 (s, 1H), 7.80 (s, 1H), 7.57 (s, 1H), 7.51-7.43 (m, 6H), 7.31-7.23 (m, 4H), 7.12-7.07 (m, 2H), 7.00-6.99 (t, J=12.0 Hz 1H), 3.75 (s, 2H), 3.58 (s, 2H), 2.25 (s, 3H), 2.14 (s, 1H) ppm. .sup.13C-NMR (100 MHz CDCl.sub.3-d): 154.31, 145.73, 139.98, 137.90, 135.90, 131.48, 130.60, 129.15, 128.39, 127.36, 126.58, 125.26, 124.61, 121.13, 120.08, 61.58, 51.88, 42.11, 17.89 ppm. MS (ESI) m/z 425.0 [MH].sup., 461.1 [M+Cl].sup..

(29) 1-(4-(4-hexyl-1H-1,2,3-triazol-1-yl)phenyl)-3-(2-(trifluoromethyl)phenyl)urea) (8d). The residue was purified by flash chromatography on silica gel (DCM/MeOH 98:2). Yield 83%, white solid. .sup.1H NMR (400 MHz, MeOD): 8.16 (s, 1H), 7.93-7.91 (d, J=8.0 Hz, 1H), 7.71-7.69 (dd, J=8.0 Hz 2H), 7.63-7.61 (dd, J=8.0 Hz, 2H), 7.59-7.55 (m, 4H), 7.27-7.23 (t, J=8.0 Hz, 1H), 2.74-2.70 (t, J=8.0 Hz 2H), 1.70-1.65 (m, 2H), 1.37-1.31 (m, 6H), 0.87 (s, 3H) ppm. .sup.13C-NMR (100 MHz, MeOD): 153.58, 148.75, 139.86, 135.97, 132.58, 131.99, 125.99, 125.66, 124.06, 122.64, 120.74, 119.77, 119.30, 31.30, 29.08, 28.57, 24.92, 22.21, 12.98 ppm. MS (ESI) m/z 432 [M+H].sup.+, 454 [M+Na].sup.+.

(30) 1-(4-(4-butyl-1H-1,2,3-triazol-1-yl)-2-methoxyphenyl)-3-(2-(trifluoromethyl)phenyl)urea (8e): The residue was purified by flash chromatography on silica gel (PE/EA 7:3). Yield 60%, white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.21-8.19 (d, J=8.8 Hz, 1H), 7.91-7.89 (d, J=8.4 Hz, 2H), 7.63 (s, 1H), 7.50-7.46 (t, J=7.8 Hz, 1H), 7.20-7.15 (m, 2H), 7.04-7.03 (d, J=1.6 Hz, 1H), 3.79 (s, 3H), 2.75-2.71 (t, J=7.6 Hz, 2H), 1.62-1.53 (m, 3H), 0.90-0.88 (d, J=6.0 Hz, 2H) ppm. .sup.13C-NMR (100 MHz, CDCl.sub.3): 154.00, 149.16, 135.94, 133.03, 128.55, 125.87, 124.30, 120.04, 118.70, 112.20, 103.47, 56.21, 38.30, 28.00, 23.74, 22.40 ppm. MS (ESI) m/z 448 [M+H].sup.+.

(31) General Procedure for the Preparation of Compounds 8 f and g

(32) L-Proline (1.9 mg, 0.01 mmol), CuCl (8.2 mg, 0.08 mmol), K.sub.2CO.sub.3, (13.7 mg, azide (20 mg, 0.08 mmol), the appropriate alkynoic acid (0.08 mmol), were sequentially added to a 10 mL glass vial equipped with a magnetic stirrer. The vial was closed with a septum and irradiated at 65 C. After 15 min., the mixture was partitioned between water 20 mL and AcOEt (40 mL), the organic layer was separated, dried (Na.sub.2SO.sub.4), and solvent removed in vacuo to furnish a brown residue, that was purified by flash chromatography on silica gel (DCM-MeOH 98:2) to give the desired triazole compounds 8e or 8f.

(33) 1-(4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl)-3-o-tolylurea (8f). The residue was purified by flash chromatography on silica gel (DCM/MeOH 98:2). Yield 77%, white solid. Yield .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.15 (s, 1H), 7.72-7.69 (d, J=8.0 Hz, 2H), 7.64-7.62 (m, 3H), 7.21-7.15 (m, 2H), 7.05-7.02 (t, J=8.0 Hz, 1H), 2.38 (s, 1H), 2.30 (s, 3H) ppm. .sup.13C-NMR (100 MHz, MeOD-d.sub.4): 53.20, 151.00, 141.20, 138.2, 133.01, 131.8, 126.08, 124.23, 123.13, 120.77, 120.28, 119.23, 16.60, 9.06 ppm. MS (ESI) m/z 306 [MH].sup., 342 [M+Cl].sup..

(34) 1-(4-(4-ethyl-1H-1,2,3-triazol-1-yl)phenyl)-3-o-tolylurea (8g). The residue was purified by flash chromatography on silica gel (DCM/MeOH 98:2). Yield 82%, white solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.21 (s, 1H), 7.73-7.71 (d, J=8.0 Hz, 2H), 7.65-7.63 (m, 3H), 7.21-7.15 (m, 2H), 7.05-7.02 (t, J=8.0 Hz, 1H), 2.82-2.76 (q, J=6.0 Hz, 2H), 2.30 (s, 3H), 1.35-1.31 (t, 8.0 Hz, 3H), ppm. .sup.13C-NMR (100 MHz, MeOD-d.sub.4): 152.60, 149.76, 140.30, 137.38, 131.86, 130.21, 128.32, 126.25, 123.33, 121.92, 120.59, 118.95, 118.77, 18.75, 17.20, 13.17 ppm. MS (ESI) m/z 320 [MH].sup., 356 [M+Cl].sup..

Example 2

(35) ##STR00054##

(36) 1-(4-methylpyridin-3-yl)-3-(4-nitrophenyl)urea (11). 9 (500 mg, 3.62 mmol) was added to a solution of o-tolyl-isocyanate 10 (673 L, 5.43 mmol) in anhydrous CH.sub.2Cl.sub.2 (10 mL) in one portion. The solution was stirred for 6 hours at r.t under a nitrogen atmosphere. The yellow precipitate was filtered, washed with cool DCM and petroleum ether and dried under high vacuum to afford the desired product 11 as a white solid. Yield=93%; .sup.1H NMR (400 MHz, DMSO d-.sub.6): 9.7 (s, 1H, NH), 8.19-8.16 (d, J=9.2 Hz, 2H), 8.13 (s, 1H), 7.78-7.76 (d, J=8.0 Hz, 1H), 7.69-7.66 (d, J=12.0 Hz, 2H), 7.19-7.13 (m, 2H), 7.00-6.97 (t, 1H, J=12.0 Hz), 2.24 (s, 3H) ppm. MS (ESI) m/z 272 [M+H].sup.+, 306 [M+Cl].sup..

(37) 1-(4-methylpyridin-3-yl)-3-(4-nitrophenyl)urea (12). Urea 11 (500 mg, 1.8 mmol) was solubilized in 30 mL of anhydrous MeOH, and 10% Palladium on charcoal (50 mg) was added. The reaction mixture was stirred under Hydrogen atmosphere for 2 hr, then the mixture was filtered off on a celite pad, and purified by flash chromatography on silica gel (DCM-MeOH 98:2). Yield=80%; white solid. .sup.1H NMR (400 MHz, DMSO d-.sub.6): 8.48 (s, 1H), 7.83-7.81 (d, J=8.0 Hz, 2H), 7.67 (s, 1H), 7.15-7.05 (m, 4H), 6.89-6.87 (d, J=8.0 Hz, 1H), 6.50-6.48 (d, J=8.0 Hz, 2H), 4.72 (s, 2H), 2.20, (s, 3H) ppm. MS (ESI) m/z 242.0 [M+H]+, 264 [M+Na].sup.+, 505 [2M+Na].sup.+.

(38) 1-(4-azidophenyl)-3-(4-methylpyridin-3-yl)urea (13). To a stirred suspension of amine 12 (400 mg, 1.6 mmol) in a 25% aq. solution of H.sub.2SO.sub.4, at 0 C., was added NaNO.sub.2 (227.9 mg, 3.3 mmol) in water, dropwise during 20 min. After this time a solution of NaN.sub.3 (208 mg, 3.2 mmol) in water (3 mL) was added dropwise during 20 min at 0 C., then the reaction mixture was stirred at r.t. Four hours later a solution of aq. NaOH was added and the pH basified until 10. The reaction mixture was then extracted with EtOAc (340 mL), washed with brine, and dried over anhydrous Na.sub.2SO.sub.4. The solvent was removed at reduced pressure and the residue was purified by flash chromatography on silica gel (DCM-MeOH 9:1). Yield 67%. .sup.1H NMR (400 MHz, CDCl.sub.3-d) 9.10 (s, 1H), 7.91 (s, 1H), 7.80-7.78 (d, J=8.0 Hz, 1H), 7.50-7.48 (d, J=8.0 Hz, 2H), 7.16-7.19 (m, 2H), 7.04-7.02 (d, J=8.0 Hz, 2H), 7.95-7.91 (t, J=8.0 Hz, 1H), 2.22 (s, 3H) ppm. MS (ESI) m/z 267 [M+Na].sup.+, 557 [2M+Na].sup.+.

(39) General Procedure for the Preparation of Compounds 15a-b

(40) The appropriate alkyne (0.10 mmol) and azide 13 (25 mg, 0.09 mmol) were suspended in a 1:1 mixture of water and t-BuOH (1.5 mL each) in a 10 mL glass vial equipped with a small magnetic stirring bar. To this, sodium ascorbate (0.1 equiv) and copper(II) sulfate pentahydrate (0.10 mmol) were added. The mixture was then heated for 5 min. at 80 C. under microwave irradiation, using an irradiation power of 300 W. After this time the precipitate was filtered-off and purified on silica, to give final products 15a or 15b.

(41) 1-(4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl)-3-(4-methylpyridin-3-yl)urea (15a). The residue was purified by flash chromatography on silica gel (DCM/MeOH 98:2). Yield 68%, white solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.87 (s, 1H), 8.20 (s, 1H), 8.15-8.14 (d, J=4 Hz, 1H), 7.74-7.71 (d, J=8.0 Hz, 2H), 7.65-7.63 (J=8.0 Hz, 2H), 7.30-7.29 (d, J=4 Hz, 1H), 4.70-4.67 (t, J=7.0 Hz, 2H), 2.36 (s, 3H), 2.06-1.99 (quint, J=7.0 Hz, 2H), 1.41-1.36 (q, J=6.0 Hz, 2H), 1.00-0.96 (q, J=8.0 Hz, 2H) ppm. .sup.13C-NMR (100 MHz, MeOD-d.sub.4): 164.69, 153.67, 143.82, 143.19, 141.39, 140.12, 134.50, 127.09, 125.50, 121.37, 118.72, 50.61, 30.06, 18.51, 14.20, 11.30 ppm. MS (ESI) m/z 320 [MH].sup., 356 [M+Cl].sup..

(42) 1-(4-(4-isopentyl-1H-1,2,3-triazol-1-yl)phenyl)-3-(4-methylpyridin-3-yl)urea (15b). The residue was purified by flash chromatography on silica gel (DCM/MeOH 98:2). Yield 74%, white solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.80 (s, 1H), 8.20 (s, 1H), 8.15-8.14 (d, J=4 Hz, 1H), 7.84-7.81 (d, J=8.0 Hz, 2H), 7.67-7.65 (J=8.0 Hz, 2H), 7.34-7.31 (d, J=4 Hz, 1H), 2.78-2.74 (t, J=8.0 Hz, 2H), 2.35 (s, 3H), 1.63-1.60 (m, 3H), 0.97-0.95 (d, J=8.0 Hz, 2H) ppm. .sup.13C-NMR (100 MHz, MeOD-d.sub.4): 64.69, 153.67, 143.82, 143.19, 141.39, 140.12, 134.50, 127.09, 125.50, 121.37, 118.72, 38.28, 27.38, 22.87, 21.32, 16.59 ppm. MS (ESI) m/z 363 [MH].sup., 399 [M+Cl].sup..

Example 3

(43) ##STR00055##

(44) 1-azido-4-nitrobenzene (16). 4-nitroaniline 2 (1000 mg, 7.24 mmol) was dissolved in CH.sub.3CN and cooled to 0 C. in an ice-salt bath. To this stirred solution, was added tBuONO (1033 L, 8.69 mmol), and the mixture was stirred for 10 min, after this time, TMSN.sub.3 (1441 L, 10.86 mmol) was added dropwise, during 10 minutes, and the resulting brown solution was stirred at r.t. One hour later the solvent was removed at reduced pressure and the residue was purified by flash chromatography on silica gel (EP-EtOAc 9:1). Yield 99%. .sup.1H NMR (400 MHz, CDCl.sub.3-d) 9.10 (s, 1H), 7.91 (s, 1H), 7.80-7.78 (d, J=8.0 Hz, 1H), 7.50-7.48 (d, J=8.0 Hz, 2H), 7.16-7.19 (m, 2H), 7.04-7.02 (d, J=8.0 Hz, 2H), 7.95-7.91 (t, J=8.0 Hz, 1H), 2.22 (s, 3H) ppm. MS (ESI) m/z 165 [M+H].sup.+, 188 [M+Na].sup.+.

(45) General Procedure for the Preparation of Compounds 17a-h

(46) The appropriate alkyne 30a-h (4.34 mmol) and azide 16 (594.11 mg, 3.62 mmol) were suspended in a 1:1 mixture of water and t-BuOH (1.5 mL each) in a 10 mL glass vial equipped with a small magnetic stirring bar. To this, was added sodium ascorbate (1.81 mmol) and copper(II) sulfate pentahydrate (1.81 mmol). The mixture was then heated for 10 min. at 120 C. under microwave irradiation, using an irradiation power of 300 W. After this time the precipitate was filtered-off and purified on silica, to give the desired triazole compounds 17a, 17b, 17c, 17d, 17e, 17f, 17g or 17h.

(47) 4-butyl-1-(4-nitrophenyl)-1H-1,2,3-triazole (17a). (Purification eluent: DCM/MeOH 98:2). Yield 80%, yellow solid. Yield .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.48 (s, 1H), 8.42-8.44 (d, J=8.0 Hz, 2H), 8.12-8.10 (d, J=8.0 Hz, 2H), 2.80-2.77 (t, J=7.6 Hz, 2H), 1.74-1.78 (q, J=7.3 Hz, 2H), 1.46-1.40 (q, J=7.3 Hz, 2H), 0.99-0.952 (t, J=7.2 Hz, 3H) ppm. MS (ESI) m/z 245 [MH].sup., 281 [M+Cl].sup..

(48) 4-isopentyl-1-(4-nitrophenyl)-1H-1,2,3-triazole (17b). (Purification eluent: PE/EtOAc 9:1). Yield 86%, yellow solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.45-8.39 (m, 3H), 8.11-8.09 (dd, J=8.0 Hz, 2H), 2.81-2.77 (t, 7.6 Hz, 2H), 1.64-1.61 (m, 3H), 0.98-0.96 (d, J=7.4 Hz, 2H) ppm. MS (ESI) m/z 260.9 [M+H].sup.+.

(49) 1-(4-nitrophenyl)-4-(perfluorobutyl)-1H-1,2,3-triazole (17c). (Purification eluent: PE/EA 95:5). Yield 73%, white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.48-8.46 (dd, J=8.1 Hz, 2H), 8.42 (s, 1H), 8.05-8.03 (dd, J=8.1 Hz, 2H) ppm. MS (ESI) m/z 442.9 [M+Cl].sup..

(50) 3-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)propanoic acid (17d). (Purification eluent: DCM/MeOH 98:2). Yield 70%, yellow solid. .sup.1H NMR (400 MHz, Acetone-d6): 8.52 (s, 1H), 8.43-8.41 (dd, J=8.0 Hz, 2H), 8.18-8.16 (dd, J=8.0 Hz, 2H), 3.06-3.03 (t, J=12.0 Hz, 2H), 2.78-2.74 (t, J=8.0 Hz, 2H) ppm. MS (ESI) m/z 261 [MH].sup..

(51) 4-(2-ethoxymethyl)-1-(4-nitrophenyl)-1H-1,2,3-triazole (17e). (Purification eluent: DCM/MeOH 98:2). Yield 80%, light yellow solid. .sup.1H NMR (400 MHz CDCl.sub.3-d): 8.34-8.31 (d, J=8.8 Hz, 2H), 8.14 (s, 1H), 7.95-7.93 (d, J=8.8 Hz, 2H), 4.65 (s, 2H), 3.61-3.56 (q, J=6.9 Hz, 2H), 1.20-1.16 (t, J=7 Hz, 3H) ppm. MS (ESI) m/z 283.2 [M+Cl].sup..

(52) 4-(2-methoxyethyl)-1-(4-nitrophenyl)-1H-1,2,3-triazole (17f). (Purification eluent: DCM/MeOH 98:2). Yield 78%, pale yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.40-8.38 (d, J=8.0 Hz, 2H), 7.97-7.95 (d, J=8.4 Hz, 2H), 3.74-3.71 (t, J=6.0, 2H), 3.38 (s, 3H), 3.10-3.07 (t, J=6.0, 2H) ppm. MS (ESI) m/z 283.2 [M+Cl].sup..

(53) 2-((benzoyloxy)methyl)-5-((1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy)tetrahydrofuran-3,4-diyl dibenzoate (17g). (Purification eluent: DCM/MeOH 98:2). Yield 86%, foam. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.31-8.29 (d, J=8.0 Hz, 2H), 8.12 (s, 1H), 7.99-7.95 (m, 4H), 7.92-7.89 (d, J=8.1 Hz, 2H), 7.85-7.83 (d, J=8.0 Hz, 2H), 7.54-7.29 (m, 5H), 7.29-7.25 (m, 4H), 5.87-5.86 (m, 1H), 5.73-5.72 (m, 1H), 5.43 (s, 1H), 4.99-4.96 (d, J=12 Hz, 1H), 4.84-4.74 (m, 3H), 4.58-4.54 (m, 1H) ppm. MS: m/z 270.9 [M+Na].sup.+

(54) 4-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)butan-2-one (17h). (Purification eluent: DCM/MeOH 98:2). Yield 74%, pale yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.32 (d, J=9.0 Hz, 1H), 7.91-7.88 (m, 2H), 3.32-2.77 (m, 4H), 2.12 (s, 3H). MS (ESI) m/z 259.1 [MH].sup..

(55) 2-(hydroxymethyl)-5-((1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methoxy)tetrahydrofuran-3,4-diol (18g). Compound 17g (155 mg, 0.23 mmol) was dissolved in 4:1 methanol/concentrated ammonium hydroxide (15 mL) and stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo and azeotroped 3 times with ethanol. The crude product was dissolved in water (5 mL), extracted with methylene chloride (350 mL) and the aqueous layer concentrated in vacuo. Yield 99%. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.64 (s, 1H), 8.43-8.41 (dd, J=8.0 Hz, 2H), 8.14-8.12 (dd, J=8.0 Hz, 2H), 5.46 (s, 1H), 5.13-5.11 (d, J=8.0 Hz, 1H), 4.70-4.67 (d, J=12 Hz, 1H), 4.13-4.11 (m, 1H), 3.98-3.91 (m, 2H), 3.78-3.66 (m, 1H), 3.60-3.56 (m, 1H) ppm. MS: m/z 375 [M+Na].sup.+

(56) General Procedure for the Preparation of Compounds 19a-h

(57) The opportune triazole compound 17 a-f, or 18g (400 mg, 1.60 mmol) was solubilized in 30 mL of anhydrous MeOH, and 10% Palladium on charcoal (25 mg) was added. The reaction mixture was stirred under Hydrogen atmosphere for 1 h, then the mixture was filtered off on a celite pad, the solvent evaporated at reduced pressure and the residue purified by flash chromatography on silica gel with the opportune eluent.

(58) 4-butyl-1-(4-aminophenyl)-1H-1,2,3-triazole (19a). (Purification eluent: DCM/MeOH 95:5). Yield 80%, white solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 7.98 (s, 1H), 7.43-7.41 (d, J=8.0 Hz, 2H), 6.78-6.76 (d, J=8.0 Hz, 2H), 2.72-2.68 (t, J=7.6 Hz, 2H), 1.70-1.64 (q, J=7.5 Hz, 2H), 1.40-1.35 (q, J=6.7 Hz, 2H), 0.95-0.90 (t, J=7.1 Hz, 3H) ppm. MS (ESI) m/z 217 [M+H].sup.+, 240 [M+Na].sup.+.

(59) 4-isopentyl-1-(4-aminophenyl)-1H-1,2,3-triazole (19b). (Purification eluent: DCM/MeOH 98:2). Yield 86%, yellow solid. Yield .sup.1H NMR (400 MHz, CDCl.sub.3-d): 7.99 (s, 1H), 7.43-7.41 (dd, J=7.8 Hz, 2H), 6.78-6.76 (dd, J=7.8 Hz, 2H), 4.84 (s, 2H), 2.74-2.70 (t, J=7.6 Hz, 2H), 1.59-1.56 (m, 3H), 0.94-0.92 (d, J=7.4 Hz, 2H) ppm. MS (ESI) m/z 245 [MH].sup., 281 [M+Cl].sup..

(60) 4-(4-(perfluorobutyl)-1H-1,2,3-triazol-1-yl)aniline (19c). The product was obtained as a pure compound. Yield 99%, white solid. .sup.1H NMR (400 MHz, Acetone-d.sub.6): 8.94 (s, 1H), 7.61-7.59 (dd, J=8.0 Hz, 2H), 6.86-6.84 (dd, J=8.0 Hz, 2H), 5.13 (s, 2H) ppm. .sup.13C NMR (100 MHz Acetone-d.sub.6): 150.01, 136.84, 126.31, 123.92, 123.21, 118.89, 114.42, 113.29 ppm. MS (ESI) m/z 377 [MH].sup., 413 [M+Cl].sup..

(61) 3-(1-(4-aminophenyl)-1H-1,2,3-triazol-4-yl)propanoic acid. (19d) The product was obtained as a pure compound. Yield 99%, white solid. .sup.1H NMR (400 MHz, MeOD): 8.02 (s, 1H), 7.40-7.39 (dd, J=4.0 Hz, 2H), 6.75-6.74 (dd, J=4.0 Hz, 2H), 3.03-3.00 (t, J=12.0 Hz, 2H), 2.64-2.60 (t, J=8.0 Hz, 2H) ppm. MS (ESI) m/z 233 [M+H].sup.+, 255 [M+Na].sup.+.

(62) 4-(2-ethoxymethyl)-1-(4-aminophenyl)-1H-1,2,3-triazole (19e). The product was obtained as a pure compound. Yield 99% white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 7.77 (s, 1H), 7.29-7.28 (d, J=8.4 Hz, 2H), 6.61-6.59 (d, J=8.4 Hz, 2H), 4.57 (s, 2H), 4.06 (s, 2H), 3.55-3.50 (q, J=6.9 Hz, 2H), 1.16-1.12 (t, J=7.0 Hz, 3H) ppm. MS (ESI): m/z 219 [M+H].sup.+.

(63) 4-(2-methoxyethyl)-1-(4-aminophenyl)-1H-1,2,3-triazole (19f). The product was obtained as a pure compound. Yield 99% white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 7.66 (s, 1H), 7.40-7.38 (d, J=8.0 Hz, 2H), 6.69-6.67 (d, J=8 Hz, 2H), 3.82 (s, 2H), 3.69-3.66 (t, J=6.4 Hz, 2H) 3.34 (s, 3H), 3.03-3.00 (t, J=6 Hz, 2H) ppm. MS (ESI): m/z 219 [M+H].sup.+.

(64) 2-(hydroxymethyl)-5-((1-(4-aminophenyl)-1H-1,2,3-triazol-4-yl)methoxy)tetrahydrofuran-3,4-diol (19g). The product was obtained as a pure compound. Yield 99% Foam. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.20 (s, 1H), 7.41-7.39 (dd, J=8.0 Hz, 2H), 6.76-6.74 (dd, J=8.0 Hz, 2H), 5.01 (s, 1H), 4.66-4.63 (d, J=12 Hz, 1H), 4.15, 4.12 (m, 1H), 4.01-3.98 (m, 1H), 3.96-3.95 (m, 1H), 3.79-3.75 (m, 1H), 3.62-3.57 (m, 1H) ppm. MS (ESI): m/z 345 [M+H].sup.+.

(65) 4-(1-(4-aminophenyl)-1H-1,2,3-triazol-4-yl)butan-2-one (19h): The product was obtained as a pure compound. Yield 99% white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d) 7.60 (s, 1H), 7.39 (d, J=8.6 Hz, 2H), 6.71 (d, J=8.6 Hz, 2H), 3.80 (s, 2H), 3.00 (t, J=6.7 Hz, 2H), 2.91 (t, J=6.7 Hz, 3H), 2.14 (s, 3H). ppm. MS (ESI): m/z 231.1 [M+H].sup.+.

(66) General Procedure for the Preparation of Compounds 20-22a-h

(67) The opportune aniline 19 a-h (100 mg, 0.46 mmol) was added to a solution of the appropriate isocyanate (85 L, 0.65 mmol) in anhydrous CH.sub.2Cl.sub.2 (10 mL) in one portion. The solution was stirred for 4 hours at r.t. under a nitrogen atmosphere. The solvent was removed, at reduced pressure and the residue purified by flash chromatography using the opportune eluent.

(68) 1-(4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl)-3-o-tolylurea (20a). (Purification eluent: DCM/MeOH 98:2). Yield 85%, white solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.18 (s, 1H), 7.72-7.70 (d, J=8.0 Hz, 2H), 7.63-7.61 (d, J=8.0 Hz, 2H), 7.20-7.16 (m, 2H), 7.05-7.01 (t, J=5.0 Hz, 1H), 2.78-2.74 (t, J=5.0 Hz, 2H), 2.3 (d, J=8.0 Hz, 2H). .sup.13C-NMR (100 MHz, MeOD-d.sub.4): 153.09, 140.57, 137.65, 131.33, 130.69, 128.42, 126.62, 123.44, 121.86, 121.09, 120.49, 119.08, 31.41, 25.18, 22.17, 18.34, 14.15 ppm. MS (ESI) m/z 348 [MH].sup., 384 [M+Cl].sup..

(69) 1-(4-(4-isopentyl-1H-1,2,3-triazol-1-yl)phenyl)-3-o-tolylurea (20b). (Purification eluent: DCM/MeOH 98:2). Yield 89%, white solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.18 (s, 1H), 7.71-7.69 (d, J=8.0 Hz, 2H), 7.64-7.61 (m, 3H), 7.2-7.1 (m, 2H), 7.04-7.01 (t, J=8.0 Hz, 1H), 2.78-2.74 (t, J=8.0 Hz, 2H), 2.29 (s, 3H), 1.63-1.60 (m, 3H), 0.97 (s, 6H), ppm. .sup.13C-NMR (100 MHz, MeOD-d.sub.4): 155.0, 150.71, 144.20, 140.26, 132.41, 130.09, 128.32, 126.08, 124.22, 123.12, 120.79, 119.76, 119.23, 38.28, 27.38, 22.87, 21.32, 16.59 ppm. MS (ESI) m/z 362 [MH].sup., 398 [M+Cl].sup..

(70) 1-(4-(4-(perfluorobutyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-(o-tolypurea (20c). (Purification eluent: DCM/MeOH 98:2). Yield 70%, white solid. .sup.1HNMR (400 MHz, MeOD-d.sub.4): 9.13 (s, 2H), 7.82-7.79 (dd, J=8.1 Hz, 2H), 7.70-7.68 (dd, J=8.1 Hz, 2H), 7.21-7.15 (m, 3H), 7.06, 7.02 (t, J=8.2 Hz, 1H), 2.30 (s, 3H) ppm. .sup.13CNMR (100 MHz, MeOD-d.sub.4): 54.16, 141.22, 136.08, 130.84, 130.07, 126.15, 124.43, 123.43, 121.48, 119.03, 115.86, 112.69, 110.20, 107.28, 16.93 ppm. .sup.19FNMR (280 MHz, MeOD-d.sub.4): 83.03, 110.64, 124.80, 127.30 ppm MS (ESI) m/z 510 [MH].sup., 545.9 [M+Cl].sup..

(71) 3-(1-(4-(3-(2-(trifluoromethyl)phenyl)ureido)phenyl)-1H-1,2,3-triazol-4-yl)propanoic acid (20d). The residue was purified by flash chromatography on silica gel (DCM/MeOH 95:5). Yield 65%, white solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.20 (s, 1H), 7.92-7.90 (d, J=8.0 Hz, 1H), 7.72-7.62 (m, 5H), 7.60-7.57 (t, J=12.0 Hz, 1H), 7.30-7.26 (t, J=8.0 Hz, 1H), 3.05-3.02 (t, J=12.0 Hz, 2H), 2.72-2.69 (t, 2H) ppm. MS (ESI) m/z 418 [MH].sup..

(72) 1-(4-(4-(ethoxymethyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-(o-tolypurea (20e). (Purification eluent: DCM/MeOH 95:5). Yield 83%, white solid. .sup.1HNMR (400 MHz, MeOD-d.sub.4): 8.41 (s, 1H), 7.73-7.64 (m, 5H), 4.59 (s, 2H), 3.64-3.59 (q, J=6.9 Hz, 2H), 2.30 (s, 3H), 1.23-1.20 (t, J=6.7 Hz, 3H) ppm. .sup.13C NMR (100 MHz, MeOD-d.sub.4) 153.69, 144.40, 140.44, 134.71, 132.83, 131.00, 129.85, 129.41, 125.84, 121.65, 120.1, 115.08, 65.65, 63.12, 16.45, 14.27 ppm. MS (ESI): m/z 351.9[M+H].sup.+

(73) 1-(4-(4-(2-methoxyethyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-o-tolylurea (20f). (Purification eluent: DCM/MeOH 95:5). Yield 78%, white solid. .sup.1HNMR (400 MHz, CDCl.sub.3-d): 8.22 (s, 1H), 7.73-7.67 (d, J=8.0 Hz, 2H), 7.65-7.62 (m, 3H), 7.21-7.15 (d, J=8.0 Hz, 2H), 7.05-7.01 (t, J=8.0 Hz, 1H), 3.72-3.69 (t, J=6.0 Hz, 2H), 3.03-3.0 (t, J=6.0 Hz, 2H), 2.30 (s, 3H), .sup.13C NMR (100 MHz, CDCl.sub.3-d): 145.76, 140.09, 130.10, 126.08, 124.24, 123.14, 120.84, 120.68, 119.24, 70.97, 57.42, 25.61, 16.60 ppm. MS (ESI): m/z 351.9 [M+H].sup.+

(74) 1-(4-(4-(3-oxobutyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-(o-tolypurea (20h): (Purification eluent: DCM/MeOH 95:5). Yield 81%, white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d) 8.08 (s, 1H), 7.85-7.67 (m, 2H), 7.20-7.02 (m, 3H), 6.91 (s, 1H), 6.88-6.69 (m, 2H), 6.38 (d, J=6.8 Hz, 2H), 3.09-2.98 (m, 2H), 2.96-2.85 (m, 2H), 2.22-2.14 (m, 6H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3-d) 206.98, 153.62, 137.21, 136.75, 131.73, 129.47, 127.74, 124.73, 123.07, 123.07, 122.19, 122.17, 121.34, 41.35, 28.57, 20.36, 17.35 ppm. MS (ESI): m/z 362.5 [MH].sup.

(75) 1-(3-chloro-2-methylphenyl)-3-(4-(4-isopentyl-1H-1,2,3-triazol-1-yl)phenyl)urea (21b). (Purification eluent: DCM/MeOH 98:2). Yield 80%, white solid. .sup.1HNMR (400 MHz, MeOD-d.sub.4): 7.89 (s, 1H), 7.64-7.57 (m, 4H), 7.08-7.06 (d, J=8.0 Hz, 1H), 6.95-6.93 (d, J=8.0 Hz, 1H), 2.77-2.73 (t, J=7.2 Hz, 2H), 2.23 (s, 3H), 1.60-1.56 (m, 3H), 0.94-0.93 (d, J=6.0 Hz, 6H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3-d): 153.48, 149.08, 139.85, 137.69, 131.73, 131.14, 126.60, 123.47, 121.61, 121.16, 119.74 ppm. MS (ESI): m/z 396 [MH].sup.

(76) 1-(4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl)-3-(2-(trifluoromethyl)phenyl)urea (22a). (Purification eluent: DCM/MeOH 98:2). Yield 78%, white solid. .sup.1HNMR (400 MHz, MeOD-d.sub.4): 8.16 (s, 1H), 7.93-7.92 (d, J=8.0 Hz, 2H), 7.71-7.68 (m, 2H), 7.64-7.61 (m, 3H), 7.59-7.55 (t, J=7.8 Hz, 1H), 7.27-7.23 (t, J=8.0 Hz), 2.75-2.71 (t, J=7.6 Hz), 1.72-1.64 (quint J=7.5 Hz, 2H), 1.42-1.34 (sx J=7.6 Hz, 2H), 0.96-0.92 (t, J=7.6 Hz, 3H) ppm .sup.13C NMR (100 MHz, CDCl.sub.3-d): 153.67, 148.70, 139.78, 135.85, 132.39, 131.91, 125.96, 125.62, 124.03, 120.85, 119.82, 119.40, 31.30, 24.60, 21.97, 12.99 ppm. MS (ESI): m/z 402 [MH].sup..

(77) 1-(4-(4-isopentyl-1H-1,2,3-triazol-1-yl)phenyl)-3-(2-(trifluoromethyl)phenyl)urea (22b). (Purification eluent: DCM/MeOH 98:2). Yield 72%, white solid. .sup.1HNMR (400 MHz, CDCl.sub.3-d): 9.11 (s, 1H), 7.83-7.81 (m, 2H), 7.654 (s, 1H), 7.48-7.46 (m, 4H), 7.41-7.37 (t, J=8.0 Hz, 1H), 7.10-7.06 (t, J=8.0 Hz, 1H), 2.76-2.72 (t, J=7.2 Hz, 2H), 1.60-1.54 (m, 3H), 0.88-0.87 (d, J=6.0 Hz). .sup.13C NMR (100 MHz, CDCl.sub.3-d): 153.78, 149.36, 139.65, 135.58, 132.44, 131.92, 127.93, 126.53, 126.05, 125.22, 124.45, 122.48, 122.16, 121.09, 120.11, 119.37, 38.38, 27.62, 23.43, 22.27 ppm. MS (ESI): m/z 416.2 [M+H].sup.+.

(78) 1-(4-(4-(((3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-(2-(trifluoromethyl)phenyl)urea (22g). (Purification eluent: DCM/MeOH 98:2). Yield 86%, white solid. .sup.1HNMR (400 MHz, Acetone-d.sub.6): 9.05 (s, 1H), 8.43 (s, 1H), 8.13-8.11 (d, J=8.0 Hz, 1H), 7.79-7.72 (m, 5H), 7.67-7.61 (m, 2H), 7.29-7.26 (t, J=7.6 Hz, 1H), 5.03 (s, 1H), 4.85-4.82 (d, J=12 Hz, 1H), 4.69-4.66 (d, J=12 Hz, 1H), 4.23 (s, 2H), 4.08-4.06 (d, J=8.0 Hz, 1H), 3.98-3.94 (m, 2H), 3.81-3.79 (m, 1H), 3.62-3.56 (m, 1H) ppm. .sup.13C NMR (100 MHz, Acetone d-.sub.6): 152.41, 145.37, 140.16, 136.73, 1332.82, 131.91, 125.92, 125.47, 123.78, 121.56, 121.30, 120.99, 119.27, 114.23, 106.76, 84.67, 75.10, 70.93, 63.07, 60.13 ppm. MS (ESI): m/z 508 [MH].sup., 543 [M+Cl].sup..

(79) Compounds 30a and 30b were purchased from Sigma Aldrich and used without further purification.

Example 4

(80) ##STR00056##

(81) 5,5,6,6,7,7,8,8,8-nonafluoro-3-iodo-2-methyloct-3-en-2-ol (28). Compound 27 (2.04 mL 11.8 mmol) and 3 mL of CH.sub.2Cl.sub.2 were added to a stirred suspension of Zinc dust (777 mg, 11.8 mmol) in 26 (1.15 mL, 11.8 mmol). To this were added 2 drops of CF.sub.3COOH, and the mixture was stirred at r.t under hv irradiation for 1 h. After that time, the reaction mixture was filtered off on a celite pad and the solvent removed at reduced pressure to give a colourless oil. Yield 92%. .sup.1HNMR (400 MHz, CDCl.sub.3-d): 6.85-6.78 (t, J=12 Hz, 1H), 2.85 (s, 1H), 1.52-1.51 (s, 6H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3-d): 126.49, 120.64, 118.77, 115.92, 113.40, 87.36, 71.79, 29.35 ppm. MS (ESI): m/z 429 [MH].sup.

(82) 5,5,6,6,7,7,8,8,8-nonafluoro-2-methyloct-3-yn-2-ol (29). To a stirring solution of KOH (434 mg, 7.7 mmol) in a mixture of EtOH (20 mL) and water (5 mL) 28 (3330 mg, 7.7 mmol) was added dropwise. The reaction mixture was stirred at r.t for 2 h, after then HCl was added, and the pH adjusted to 7. Et.sub.2O was added and the reaction mixture extracted several times and dried over anhydrous Na.sub.2SO.sub.4. Yield 90%, yellow oil. .sup.1HNMR (400 MHz, CDCl.sub.3-d): 1.49, (s, 6H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3-d): 120.49, 118.68, 115.88, 113.38, 111.10, 82.10, 76.49, 64.83, 29.10 ppm. MS (ESI): m/z 431 [MH].sup.

(83) 3,3,4,4,5,5,6,6,6-nonafluorohex-1-yne (30c). Compound 29 (2114 mg, 7 mmol) was added to a solution of 280 mg of NaOH in water. The mixture was heated and immediately distilled (b.p. 40 C.). Yield 78%. Colourless oil. .sup.1HNMR (400 MHz, CDCl.sub.3-d): 2.16, (s, 1H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3-d): 117.0, 108.12, 107.50, 80.32, 71.63 ppm. MS (ESI): m/z 243 [MH].sup.

Example 5

(84) ##STR00057##

(85) pent-4-ynoic acid (30d). 23d (1 mL, 10.7 mmol) was dissolved in Acetone and cooled to 0 C. Jones reagent was added dropwise to the solution, under vigorous stirring, until the reaction mixture remained orange. The mixture was allowed to reach r.t., and more Jones reagent was added to maintain the orange colour. The reaction mixture was stirred at r.t. for 1 h, then water was added, and was extracted with Et.sub.2O several times, washed with Brine and dried over anhydrous Na.sub.2SO.sub.4. The solvent was removed at reduced pressure and the resulting oil purified by flash chromatography on silica gel (Hexane/Et.sub.2O 8:2). Yield 82%, colourless oil. .sup.1HNMR (400 MHz CDCl.sub.3-d): 2.61-2.59 (m, 2H), 2.52-2.48 (m, 2H), 1.98-1.95 (m, 1H) ppm.

(86) General Procedure for the Preparation of Compounds 30e and 30f

(87) To a stirring solution of 200 g of NaOH in 300 mL of water (0.3 mol, 16.8 g) was added the opportune alcohol (2.5 mL, 33.02 mmol). To this, was slowly added the corresponding sulfate (15 mmol, 2082 mg) in 2 h dropwise and the mixture was heated at 50 C. The final product was distilled off, the distillation was stopped at 95 C., then the content of the receiver was washed with cold NH.sub.4Cl aq solution and separated.

(88) 3-ethoxyprop-1-yne (30e). Yield 68% colourless oil. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 4.13-4.13 (d, J=2.4 Hz, 2H), 3.60-3.55 (q, 2H), 2.41-2.40 (t, J=4.8 Hz, 1H), 1.24-1.22 (t, J=4 Hz, 3H) ppm

(89) 4-methoxybut-1-yne (30f). Yield 52% colourless oil. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 3.52-3.49 (m, 2H), 3.33 (s, 3H), 2.47-2.43 (m, 2H), 1.99-1.97 (m, 1H) ppm.

(90) 1-propynyl-2,3,4-tri-O-benzoyl-ribofuranose (30g): To a solution of 0-D-ribofuranose 1-acetate 2,3-5 tribenzoate (937 mg, 1.8 mmol) in dichloromethane (8 mL) was added propargyl alcohol (129 l, 2.23 mmol) and BF.sub.3.Et.sub.2O (344 L, 2.79 mmol) at 0 C. and the reaction mixture was stirred at room temperature for 2 h. After this time, K.sub.2CO.sub.3 (450 mg) was added and stirring was continued for further 15 min. Then the reaction mixture was filtered and washed with dichloromethane. The filtrate was washed with water, the aqueous phase was separated and extracted with dichloromethane (320 mL) and the combined organic phases were dried (Na.sub.2SO.sub.4) and concentrated to yield the desired compound 30g as a crystalline solid. Yield 85%. .sup.1H NMR (400 MHz CDCl.sub.3-d): 8.07-7.00 (m, 4H), 7.87-7.85 (d, J=8.1 Hz, 2H), 7.55-7.43 (m, 3H), 7.41-7.34 (m, 4H), 7.29-7.25 (m, 2H), 5.93-5.90 (m, 1H), 5.77-5.76 (d, J=4.2 Hz, 1H), 5.50 (s, 1H), 4.70-4.65 (m, 2H), 4.50-4.46 (m, 1H), 4.20 (s, 2H), 2.45 (s, 1H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3-d): 166.10, 165.26, 165.07, 133.44, 133.33, 133.10, 129.75, 129.67, 129.11, 128.84, 128.43, 128.34, 128.29, 103.30, 79.30, 78.25, 75.48, 75.24, 72.07, 64.42, 54.49 ppm. MS (ESI) m/z: 523 [M+Na].sup.+.

(91) hex-5-yn-2-one (30h): A mixture of propargyl chloride (485 L, 6.71 mmol), acetylacetone (758 L, 7.38 mmol) and K.sub.2CO.sub.3 (1112 mg, 8.0 mmol) was stirred in EtOH (10 mL), at 80 C., for 12 h. After this time, EtOH was partially removed under reduced pressure, water (15 mL) was added, the aqueous phase was separated and extracted with MTBE (320 mL). The combined organic phases were dried (Na.sub.2SO.sub.4). 30 h was finally purified by distillation bp=71 C. .sup.1H NMR (400 MHz, CDCl.sub.3) 2.66 (t, J=7.1 Hz, 1H), 2.41 (t, J=5.9 Hz, 1H), 2.14 (s, 1H), 1.92 (s, 1H) ppm.

Example 6

(92) ##STR00058##

(93) General Procedure for the Preparation of Compounds 31a-e

(94) The appropriate alkyne (6.08 mmol) and azide 16 (831 mg, 5.07 mmol) were suspended in a 1:1 mixture of water and t-BuOH (1.5 mL each) in a 10 mL glass vial equipped with a small magnetic stirring bar. To this, was added sodium ascorbate (2.5 mmol) and copper(II) sulfate pentahydrate (2.50 mmol). The mixture was then heated for 10 min. at 125 C. under microwave irradiation, using an irradiation power of 300 W. After that time the solvent was removed at reduced pressure water was added and the mixture was extracted with EtOAc (320 mL). The organic layers were collected, washed with Brine and dried over Na.sub.2SO.sub.4. The crude was purified by flash chromatography on silica gel using the opportune eluent to give the desired triazole compounds 31a, 31b, 31c, 31d or 31e.

(95) (1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methanol (31a). (Purification eluent: DCM/MeOH 98:2). Yield 90%, yellow solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.47 (s, 1H), 8.42, 8.40 (d, J=8.0 Hz, 2H), 8.12, 8.09 (d, J=8.0 Hz, 2H), 2.34 (s, 2H) ppm. MS (ESI) m/z 221 [M+H].sup.+, 243 [M+Na].sup.+.

(96) (1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)ethanol (31b). (Purification eluent: DCM/MeOH 98:2). Yield 84%, yellow solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.50 (1H, NCH), 8.44-8.42 (d, J=8.0 Hz, 2H), 8.14-8.12 (d, J=8.0 Hz, 2H), 3.90-3.87 (t, J=6.0 Hz, 2H), 3.02-2.99 (t, J=6.0 Hz, 2H) ppm. MS (ESI) m/z 235 [M+H].sup.+, 257 [M+Na].sup.+.

(97) (1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)propanol (31c). (Purification eluent: DCM/MeOH 98:2). Yield 88%, yellow solid .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.47 (s, 1H), 8.42, 8.40 (d, J=8.0 Hz, 2H), 8.12, 8.09 (d, J=8.0 Hz, 2H), 3.66-3.63 (t, J=6.0 Hz, 2H), 2.89-2.85 (t, J=8.0 Hz, 2H), 1.98-1.92 (t, J=8.0 Hz, 2H). MS (ESI) m/z 227 [M+H].sup.+, 271 [M+Na].sup.+.

(98) 4-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)butan-1-ol (31d). (Purification eluent: DCM/MeOH 98:2). Yield 85%, yellow solid .sup.1H NMR (400 MHz, MeOD-d.sub.4) 8.43 (s, 1H), 8.35 (d, J=9.0 Hz, 2H), 8.08 (m, Hz, 2H), 3.59 (t, J=6.4 Hz, 2H), 2.79 (t, J=7.6 Hz, 2H), 1.78 (q, J=15.2 Hz, 2H), 1.61 (dt, J=13.1, 6.4 Hz, 2H) ppm. MS (ESI) m/z 361[MH].sup..

(99) 2-methyl-1-(1-(4-nitro phenyl)-1H-1,2,3-triazol-4-yl)pentan-1-ol (31e). (Purification eluent: DCM/MeOH 98:2). Yield 88%, yellow solid .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.39-8.37 (d, J=8.0 Hz, 2H), 8.05 (s, 1H), 7.98-7.96 (d, J=8.0 Hz, 2H), 4.91-4.84 (m, 1H), 2.82 (s, 1H), 2.06-2.03 (m, 1H), 1.51-1.12 (m, 4H), 0.93-0.86 (m, 6H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3-d): 152.24, 147.33, 141.61, 125.52, 124.92, 120.36, 119.28, 71.60, 70.98, 38.88, 38.63, 35.06, 33.80, 20.31, 20.13, 15.25, 14.24, 13.80 ppm. MS (ESI) m/z 325.0 [M+Cl].sup..

(100) General Procedure for the Preparation of Compounds 32a-d

(101) Tosyl Chloride, (1.88 mmol, 359.00 mg), KOH (4.28 mmol, 240.39 mg), and the opportune alcohol, were stirred in 15 mL of anhydrous THF in an ice-salt bath, at 0 C. under nitrogen atmosphere. After 30 min. the reaction mixture was stirred at r.t. Twelve hours later the solvent was removed at reduced pressure, water was added and the reaction mixture was extracted with DCM (100 mL3). The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4), and concentrated. The residue was purified by flash chromatography on silica gel (PE/EtOAc 5:3).

(102) 3-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methyl 4-methylbenzenesulfonate (32 a). Yield 72%. White solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.44-8.41 (d, J=9.2 Hz, 2H), 8.17 (s, 1H), 7.96-7.93 (d, J=9.2 Hz, 2H), 7.84-7.82 (d, J=8.4 Hz, 2H), 7.37-7.35 (d, J=8 Hz, 2H), 5.29 (s, 2H), 2.45 (s, 3H) ppm. MS (ESI): m/z 397 [M+Na].sup.+

(103) 3-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)ethyl 4-methylbenzenesulfonate (32 b). Yield 78%. White solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.42-8.39 (d, J=9.2 Hz, 2H), 7.98 (s, 1H), 7.95-7.93 (d, J=8.8 Hz, 2H), 7.75-7.73 (d, J=8.4 Hz, 2H), 7.32-7.30 (d, J=8 Hz, 2H), 4.37-4.34 (t, J=6.4 Hz, 2H), 3.21-3.18 (t, J=6.4 Hz, 2H), 2.40 (s, 3H) ppm. MS (ESI): m/z 410.8 [M+Na].sup.+

(104) 3-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)propyl 4-methylbenzenesulfonate (32 c). Yield 83%. White solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.35-8.33 (d, J=8.8 Hz, 2H), 7.94-7.92 (m, 3H), 7.74-7.72 (d, J=8.0 Hz, 2H), 7.75-7.73 (d, J=8.4 Hz, 2H), 7.31-7.29 (d, J=8 Hz, 2H), 4.09-4.06 (t, J=6.0 Hz, 2H), 2.88-2.84 (t, J=8.0 Hz, 2H), 2.38 (s, 3H), 2.12-2.07 (quint, J=6.0 Hz, 2H ppm. MS (ESI): m/z 402.8 [M+H].sup.+, 424.8 [M+Na].sup.+

(105) 4-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)butyl 4-methylbenzenesulfonate (32d). Yield 90%. White solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.38 (d, J=9.0 Hz, 1H), 7.94 (d, J=8.9 Hz, 1H), 7.86 (s, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 4.06 (t, J=5.8 Hz, 1H), 2.80 (t, J=7.1 Hz, 1H), 2.42 (s, 2H), 1.89-1.64 (m, 3H). MS (ESI): m/z 417.1 [M+H].sup.+

(106) General Procedure for the Preparation of Compounds 33e-i.

(107) To a solution of the opportune tosylate, was added the corresponding amine, at 0 C. The reaction mixture was stirred at 80 C. in a sealed tube. After 24 h the solvent was removed at reduced pressure and the residue purified by flash chromatography on silica gel.

(108) 4-(3-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)methyl)morphine (33e). (Purification eluent: DCM-methanol 98:2). Yield 95%. White solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.6 (s, 1H), 8.46-8.44 (d, J=8 Hz, 2H), 8.17-8.14 (d, J=8.0 Hz, 2H), 3.76 (s, 2H), 3.71-3.69 (m, 4H), 2.57-2.55 (m, 4H) ppm. MS(ESI): m/z 412.9 [M+Na]+, 289.9 [M+H].sup.+.

(109) 4-(3-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)ethyl)morpholine (33f). (Purification eluent: DCM-methanol 98:2). Yield 92%. White solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.51 (s, 1H), 8.43-8.40 (d, J=8 Hz, 2H), 8.13-8.10 (d, J=8 Hz, 2H), 3.72-3.69 (m, 4H), 3.01-2.99 (t, J=2 Hz, 2H) 2.77-2.73 (t, J=8 Hz, 2H), 2.57-2.55 (m, 4H). MS (ESI): m/z 303.9 [M+H].sup.+.

(110) 4-(3-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)propyl)morpholine (33g). (Purification eluent: DCM-methanol 98:2). Yield 90%. White solid. .sup.1H NMR (400 MHz, Acetone): 8.51 (s, 1H), 8.43-8.41 (d, J=8.9 Hz, 2H), 8.19-8.16 (d, J=8.9 Hz, 2H), 3.59-3.57 (m, 4H), 2.83-2.80 (t, J=7.6 Hz, 2H) 2.40-2.36 (m, 4H), 2.57-1.93-1.86 (t, J=7.6 Hz, 2H). MS (ESI): m/z 303.9 [M+H].sup.+.

(111) 1-methyl-4-(3-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)propyl)piperazine (33h). (Purification eluent: DCM-methanol 98:2). Yield 69% white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.22-8.20 (d, J=8.0 Hz, 2H), 7.85-7.82 (m, 3H), 2.69-2.66 (t, J=6.0 Hz, 2H), 2.31-2.26 (m, 10H), 2.10 (s, 3H), 1.82-1.74 (quint, J=5.9 Hz, 2H) ppm. MS (ESI): m/z 330.9 [M+H].sup.+, 353 [M+Na].sup.+.

(112) 4-(3-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)propyl)dimethylamine (33i). (Purification eluent: DCM-methanol 95:5). Yield 69% white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.63 (s, 1H), 8.43-8.41 (d, J=8.8 Hz, 2H), 8.16-8.14 (d, J=8.8 Hz, 2H), 3.14-3.10 (t, J=6.0 Hz, 2H), 2.93-2.90 (t, J=6.0 Hz, 2H), 2.81 (s, 6H), 2.21-2.13 (quint, J=8.0 Hz, 2H) ppm. MS (ESI): m/z 317.9 [M+H].sup.+, 339.9 [M+Na].sup.+.

(113) 4-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)butan-1-amine (33l). 32d (500 mg, 1.2 mmol) was solubilized in anhydrous DCM (2 mL), in a vial. The rxn mixture was cooled to 78 C., and ammonia was bubbled in the solution. The tube was sealed and the resulting mixture was stirred at rt for 12 hrs. After this time the solvent was removed at reduced pressure. HCl 3N was added and the resulting yellow pp was filtered-off and recrystallized from ACN. Yield 80%, white solid .sup.1H NMR (400 MHz, MeOD) 8.42 (s, 1H), 8.33 (d, J=8.6 Hz, 3H), 8.04 (d, J=8.5 Hz, 3H), 2.77-2.74 (m, 4H), 1.80-1.66 (m, 2H), 1.57-1.55 (m, 2H), 0.81 (m, 2H) ppm. MS (ESI): m/z 262 [M+H].sup.+, 284 [M+Na].sup.+.

(114) tert-butyl (4-(1-(4-nitro phenyl)-1H-1,2,3-triazol-4-yl)butyl)carbamate (33m): 33l (110 mg, 0.42 mmol) and Boc.sub.2O (139 mg, 0.63 mmol), were stirred in a mixture of 5% NaOH(aq) 10 mL, and THF (10 mL) at rt for 8 hrs. After this time the solvent was removed at reduced pressure and the pH adjusted to 6 by addition of 1N HCl. The reaction mixture was extracted with EtOAc (100 mL3). The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4), and concentrated. The residue was purified by flash chromatography on silica gel (DCM/MeOH 98:2). Yield 93% white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.35 (d, J=7.5 Hz, 1H), 7.95-7.92 (m 2H), 4.61 (s, 1H), 3.13-3.10 (m 2H), 2.78 (m, 2H), 1.75-1.70 (m, 211), 1.49-1.43 (m, 2H), 1.39 (s, 9H) ppm.

(115) General Procedure for the Preparation of Compounds 34a-i and m.

(116) The opportune triazole compound 31a-d, or 33e-i (400 mg, 1.60 mmol) was solubilized in 30 mL of anhydrous MeOH, and 10% Palladium on charcoal (25 mg) was added. The reaction mixture was stirred under Hydrogen atmosphere for 1 h, then the mixture was filtered off on a celite pad, the solvent evaporated at reduced pressure.

(117) (1-(4-aminophenyl)-1H-1,2,3-triazol-4-yl)methanol (34a). Yield 99%, white solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.09 (s, 1H), 7.46-7.41 (d, J=8.0 Hz, 2H), 6.81-6.75 (d, J=8.0 Hz 2H), 2.29 (s, 2H) ppm. MS (ESI) m/z 191 [MH].sup.+, 213 [M+Na].sup.+.

(118) (1-(4-aminophenyl)-1H-1,2,3-triazol-4-yl)ethanol (34b). Yield 99%, white solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.09 (s, 1H), 7.46-7.41 (d, J=8.0 Hz, 2H), 6.81-6.75 (d, J=8.0 Hz 2H), 3.86-3.83 (t, J=6 Hz, 2H) 2.95-2.93 (t, J=6 Hz, 2H) ppm. MS (ESI) m/z 205 [M+H].sup.+, 227 [M+Na].sup.+.

(119) 1-(1-(4-aminophenyl)-1H-1,2,3-triazol-4-yl)-2-methylpentan-1-ol (34d). Yield 99%, white solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.12 (s, 1H), 7.45-7.43 (d, J=8.4 Hz, 2H), 6.79-6.77 (d, J 8.4 Hz, 2H), 4.76-4.62 (m, 1H), 1.98-1.90 (m, 1H), 1.54-1.12 (m, 4H), 0.94-0.88 (m, 6H) ppm. MS (ESI): m/z 261.3 [M+H].sup.+, 282.9 [M+Na].sup.+.

(120) 4-(4-(3-morpholinomethyl)-1H-1,2,3-triazol-1-yl)benzenamine (34e). Yield 99%, white solid. .sup.1H NMR (MeOD-d.sub.4): 8.25 (s, 1H), 7.47-7.43 (d, J=8 Hz, 2H), 6.80-6.76 (d, J=8 Hz, 2H), 3.84 (s, 2H) 3.72-3.71 (m, 4H), 2.68-2.67 (m, 4H) ppm. MS (ESI): m/z 259.9 [M+H].sup.+, 281.9 [M+Na].sup.+.

(121) 4-(4-(3-morpholinoethyl)-1H-1,2,3-triazol-1-yl)benzenamine (34f). Yield 99%, white solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.09 (s, 1H), 7.44-7.40 (d, J=8 Hz, 2H), 6.79-6.75 (d, J=8 Hz, 2H), 3.71-3.68 (m, 4H), 2.97-2.93 (t, J=8 Hz, 2H) 2.73-2.69 (t, J=8 Hz, 2H), 2.54-2.53 (m, 4H) ppm. MS: m/z 273.9 [M+H].sup.+.

(122) 4-(4-(3-dimethylaminopropyl)-1H-1,2,3-triazol-1-yl)benzenamine (34g). Yield 99%, white solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.21 (s, 1H), 7.47-7.45 (d, J=8.0 Hz, 2H), 6.82-6.80 (d, J=8.0 Hz, 2H), 3.25-3.21 (t, J=6.0 Hz, 2H), 2.90-2.85 (m, 8H), 2.15-2.18 (quint, J=8.0 Hz, 2H) ppm. MS (ESI): m/z 246.0 [M+H].sup.+.

(123) 4-(4-(3-morpholinopropyl)-1H-1,2,3-triazol-1-yl)benzenamine (34h). Yield 99%, white solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.04 (s, 1H), 7.44-7.42 (d, J=8.0 Hz, 2H), 6.78-6.76 (d, J=8 Hz, 2H), 3.67-3.64, (m, 4H), 2.74-2.72 (t, J=7.6 Hz, 2H), 2.43-2.38 (m, 6H), 1.91-1.84 (quint, J=8.0 Hz, 2H) ppm. MS (ESI): m/z 287.9 [M+H].sup.+, 309.9 [M+Na].sup.+,

(124) 4-(4-(3-methylpiperazinopropyl)-1H-1,2,3-triazol-1-yl)benzenamine (34i). Yield 99%, white solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 7.56 (s, 1H) 7.37-7.26 (d, J=8.2 Hz, 2H), 6.69-6.67 (d, J=8 Hz, 2H), 2.75-2.72 (t, J=7.6 Hz, 2H), 2.48-2.40 (m, 9H), 2.26 (s, 1H), 1.90-1.86 (quint, J=7.4 Hz, 2H) ppm. MS (ESI): m/z 301.1 [M+H].sup.+, 323.2 [M+Na].sup.+

(125) tert-butyl (4-(1-(4-aminophenyl)-1H-1,2,3-triazol-4-yl)butyl)carbamate (34m): Yield 99%, white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.57 (s, 1H), 7.39 (d, J=8.6 Hz, 2H), 6.70 (d, J=8.7 Hz, 2H), 4.62 (s, 1H), 3.12 (s, 2H), 2.74 (t, J=7.5 Hz, 2H), 1.79-1.61 (m, 2H), 1.61-1.43 (m, 2H), 1.39 (s, 9H). ppm. MS (ESI): m/z 332.4 [M+H].sup.+, 354.1 [M+Na].sup.+

(126) General Procedure for the Preparation of Compounds 35a-i.

(127) The opportune aniline 34a-i (0.10 mmol) was added to a solution of the appropriate isocyanate 1 or 24 (0.15 mmol) in anhydrous MeOH (10 mL) in one portion. The solution was stirred for 9 hours at r.t. under a nitrogen atmosphere. The solvent was removed at reduced pressure and the residue purified on silica to afford the final product 35a, 35b or 35g as white solid. Alternatively the residue was crystallized from MeOH to afford compound 35e or 35f.

(128) 1-(4-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-o-tolylurea (35a). (Purification eluent: DCM-methanol 95:5). Yield 79% white solid. .sup.1H NMR (400 MHz, DMSO d-.sub.6): 9.23 (s, 1H), 8.54 (s, 1H), 7.97 (s, 1H), 7.80-7.76 (d, J=8 Hz, 2H), 7.80-7.76 (m, 3H), 7.64-7.62 (d, J=8.0 Hz, 2H), 7.17-7.12 (m, 2H), 6.96-6.93 (t, J=6.0 Hz, 1H), 4.58 (s, 2H), 2.24 (s, 3H) ppm. .sup.13C-NMR (100 MHz, DMSO d-.sub.6): 153.09, 140.57, 137.78, 131.50, 131.09, 128.46, 127.04, 123.60, 122.38, 121.27, 120.49, 118.84, 55.44, 18.36 ppm. MS (ESI) m/z 322.1 [MH].sup., 358 [M+Cl].sup..

(129) 1-(4-(4-(hydroxyethyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-o-tolylurea (35b). (Purification eluent: DCM-methanol 95:5). Yield 75% white solid. .sup.1H NMR (400 MHz, DMSO d-.sub.6): 9.23 (s, 1H), 8.54 (s, 1H), 8.04 (1H, s), 7.80-7.76 (d, J=8.0 Hz, 2H), 7.75-7.73 (1H, d, J=8.4 Hz), 7.64-7.62 (d, J=8.0 Hz, 2H), 7.17-7.11 (2H, m), 6.96-6.93 (t, J=6.0 Hz, 1H), 3.71-3.67 (t, 6.4 Hz, 2H), 2.84-2.81 (t, J=6.8 Hz, 2H) 2.24 (s, 3H) ppm. .sup.13C NMR (100 MHz, DMSO d-.sub.6): 145.80, 140.71, 137.74, 131.44, 130.79, 128.38, 126.71, 123.47, 121.89, 121.15, 119.11, 66.75, 29.68, 18.37 ppm. MS(ESI): m/z 360 [M+Na].sup.+

(130) 1-(4-(4-(3-hydroxypropyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-(2-(trifluoromethyl)phenyl)urea (35c). (Purification eluent: DCM/MeOH 98:2). Yield 80%, white solid .sup.1H NMR (400 MHz, MeOD-d.sub.4): 7.79-7.77 (d, 1H), 7.70 (s, 1H), 7.49-7.47 (m, 3H), 7.43-7.40 (m, 3H), 7.12-7.10 (t, 1H), 3.66-3.63 (t, J=6.0 Hz, 2H), 2.89-2.85 (t, J=8.0 Hz, 2H), 1.98-1.92 (t, J=8.0 Hz, 2H). MS (ESI) m/z 407 [M+H].sup.+, 429 [M+Na].sup.+.

(131) 1-(4-(4-(3-hydroxyhexan-2-yl)-1H-1,2,3-triazol-1-yl)phenyl)-3-(2-(trifluoromethyl)phenyl) urea (35d). (Purification eluent: DCM/MeOH 98:2). Yield 77%. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 7.81-7.79 (d, 1H), 7.68 (s, 1H), 7.51-7.49 (m, 3H), 7.42-7.38 (m, 3H), 7.11-7.08 (m, 1H), 4.76-4.62 (m, 1H), 1.98-1.90 (m, 1H), 1.54-1.12 (m, 4H), 0.94-0.88 (m, 6H) ppm. MS (ESI): m/z 446 [MH].sup..

(132) 1-(4-(4-(morpholinomethyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-o-tolylurea (35e). The residue was crystallized from MeOH. Yield 69% white crystals. .sup.1H NMR (MeOD-d.sub.4): 8.37 (s, 1H), 7.75-7.73 (d, J=9.2 Hz, 2H), 7.66-7.606 (m, 3H), 7.21-7.17 (m, 2H), 7.06-7.02 t, J=7.6 Hz, 1H), 3.73 (s, 2H)), 3.71-3.69 (m, 4H) 2.565-2.54 (m, 4H), 2.30 (s, 3H) ppm. .sup.13C NMR (MeOD-d.sub.4): 144.47, 143.79, 140.39, 131.54, 130.09, 126.08, 124.23, 123.11, 122.06, 120.89, 119.23, 66.20, 52.92, 16.85 ppm. MS: m/z 392.9 [M+H].sup.+

(133) 1-(4-(4-(morpholinoethyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-o-tolylurea (35f). The residue was crystallized from MeOH. Yield 75% White solid. .sup.1H NMR (400 MHz, DMSO d-.sub.6): 9.24 (s, 1H), 8.44 (s, 1H), 7.97 (s, 1H), 7.80-7.78 (d, J=8 Hz, 2H), 7.75-7.72 (d, J=9.2 Hz, 2H), 7.63-7.61 (d, J=8.8 Hz, 2H), 7.17-7.11 (m, 3H), 6.96-6.92 (t, J=7.2 Hz, 1H), 3.57-3.55 (m, 4H) 2.87-2.83 (t, J=7.6 Hz, 3H), 2.62-2.58 (t, J=8 Hz, 2H), 2.41-2.40 (m, 4H) 2.23 (s, 3H) ppm. .sup.13C NMR (100 MHz, DMSO d-.sub.6): 145.59, 140.51, 137.64, 131.36, 130.69, 128.36, 126.64, 123.44, 121.81, 121.12, 120.72, 119.09, 66.66, 58.12, 53.62, 23.20, 18.33 ppm. MS (ESI): m/z 421.2 [M+H]+, 443 [M+Na].sup.+.

(134) 1-(4-(4-(morpholinopropyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-o-tolylurea (35g). (Purification eluent: DCM-methanol 98:2). Yield 70% white solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.23 (s, 1H), 7.73-7.71 (d, J=8.0 Hz, 2H), 7.65-7.63 (d, J=7.6 Hz, 2H), 7.21-7.15 (m, 2H), 7.05-7.02 (t, J=7.4 Hz, 1H), 3.70-3.67 (m, 4H), 2.82-2.78 (t, J=8 Hz, 2H), 2.48-2.43 (m, 6H), 2.29 (s, 1H), 1.98-1.90 (quin. J=8.0 Hz, 2H) ppm. .sup.13C NMR (100 MHz, MeOD-d.sub.4) 145.61, 140.53, 137.67, 131.38, 130.71, 128.37, 126.66, 123.48, 121.87, 121.21, 120.77, 119.21, 66.21, 58.22, 53.47, 25.78, 22.99, 18.11 ppm. MS (ESI): m/z 406.9 [M+H]+, 428.9 [M+Na].sup.+.

(135) 4-(4-(3-(4-methylpiperazin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)benzenamine (35h). (Purification eluent: DCM-methanol 99:1). Yield 69% white solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.24 (s, 1H), 7.72-7.63 (m, 4H), 7.19-7.14 (m, 2H), 7.04-7.00 (t, J=8 Hz, 1H), 2.81-2.78 (t, J=7.6 Hz, 2H), 2.63-2.60 (m, 8H), 2.52-2.48 (t, J=8 Hz, 2H), 2.36 (s, 1H), 2.30 (s, 1H), 1.98-1.91 (quint, J=7.6 Hz, 2H) ppm. .sup.13C NMR (100 MHz, MeOD-d.sub.4) 154.19, 147.95, 140.27, 136.32, 131.61, 130.03, 126.13, 124.15, 123.14, 120.73, 120.14, 120.01, 119.28, 57.08, 53.97, 51.82, 44.18, 25.78, 22.72, 16.78 ppm. MS (ESI): m/z 434 [M+H]+, 457.2[M+Na].sup.+.

(136) 1-(4-(4-(dimethylaminopropyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-o-tolylurea (35i). (Purification eluent: DCM-methanol 95:5). Yield 67% white solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.30 (s, 1H), 7.74-7.72 (d, J=8.0 Hz, 2H), 7.67-7.62 (m, 3H), 7.21-7.15 (m, 2H), 7.06-7.02 (t, J=8.0 Hz, 1H), 3.08-3.04 (t, J=8 Hz, 2H), 2.89-2.85 (t, J=7.4 Hz, 2H), 2.62-2.58 (t, J=8.0 Hz, 2H), 2.77 (s, 6H), 2.3 (s, 3H), 2.15-2.08 (quint, J=7.6 Hz, 2H), ppm. .sup.13C NMR (100 MHz, MeOD-d.sub.4): 154.17, 146.69, 140.35, 136.28, 131.54, 130.10, 126.06, 124.2, 123.10, 120.76, 120.34, 119.2, 57.27, 42.5, 29.28, 24.43, 21.97, 16.69 ppm. MS (ESI): m/z 376.9 [MH].sup., 412.9 [M+Cl].sup.

(137) diethyl (2-(1-(4-(3-(o-tolyl)ureido)phenyl)-1H-1,2,3-triazol-4-yl)ethyl) phosphate (36). 35b (35 mg, 0.10 mmol), was solubilized in 6 mL of anhydrous CH.sub.2Cl.sub.2, then (Et.sub.2O).sub.2POCl (17 L, 0.12 mmol), TEA (42 L, 0.30 mmol), and Ti(tBuO).sub.4 were added sequentially via syringe. The reaction mixture was stirred at r.t for 11 h, then the solvent was removed at reduced pressure and the residue purified by flash chromatography on silica gel. (PE-EtOAc 2:1). Yield 75% yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.37 (s, 1H), 7.70-7.68 (m, 2H), 7.48-7.38 (m, 5H), 7.20-7.12 (m, 2H), 7.02-6.98 (t, J=8.0 Hz, 1H), 4.40-4.36 (t J=8.0 Hz, 2H), 4.13-4.07 (q, J=7.6 Hz, 4H), 3.18-3.15 (t, J=6.2 Hz, 2H), 2.23 (s, 3H), 1.32-1.29 (t, J=7.0 Hz, 3H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3-d): 153.60, 143.78, 140.09, 136.29, 131.37, 130.69, 130.42, 129.97, 126.87, 126.62, 124.50, 123.44, 120.95, 120.12, 119.53, 66.42, 66.25, 27.06, 17.90, 16.03 ppm. MS (ESI): m/z 472 [MH].sup., 508 [M+Cl].sup.

(138) General Procedure for the Preparation of Compounds 37-39.

(139) The opportune alcohol 35b-c, (25 mg, 0.07 mmol), acid (10 L, 0.07 mmol), N,N-dicyclohexylcarbodiimide (22 mg, 0.11 mmol), and DMAP (3 mg, 0.01 mmol), were stirred at 0 C. for 30 min. in a mixture of CH.sub.2Cl.sub.2 10 mL and DMF 2 mL. After that time, the reaction mixture was allowed to reach r.t. and stirred for 12 h. The solvent was then removed at reduced pressure, EtOAc was added and the mixture was washed with 5% LiCl aq. Solution, dried over anhydrous Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with the opportune eluent.

(140) 2-(1-(4-(3-(o-tolyl)ureido)phenyl)-1H-1,2,3-triazol-4-yl)ethyl 3-methylbutanoate (37). (Purification eluent: DCM-methanol 98:2). Yield 74% white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 7.72 (s, 1H), 7.56-7.48 (m, 5H), 7.25-7.23 (m, 3H), 7.17-7.14 (m, 2H), 6.61 (s, 1H), 4.41-4.38 (t, J=6.6 Hz, 2H), 3.14-3.11 (t, J=6.6 Hz, 2H), 2.28 (s, 3H), 2.18-2.16 (d, J=7.6 Hz, 2H), 0.92-0.89 (d, J=6.8 Hz, 6H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3): 173.05, 153.62, 144.95, 139.21, 136.93, 135.65, 136.19, 132.73, 132.18, 131.54, 131.00, 127.53, 126.98, 126.62, 125.34, 121.28, 120.30, 119.94, 62.75, 43.32, 25.57, 22.45, 17.88 ppm. MS (ESI): m/z 420 [MH].sup., 456 [M+Cl].sup.

(141) 2-(1-(4-(3-(2-(trifluoromethyl)phenyl)ureido)phenyl)-1H-1,2,3-triazol-4-yl)ethyl 3-methylbutanoate (38). (Purification eluent: DCM-methanol 98:2). Yield 68% white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.19 (s, 1H), 7.98-7.96 (d, J=8 Hz, 1H), 7.76 (s, 1H), 7.58-7.50 (m, 5H), 7.38 (s, 1H), 7.21-7.17 (t, J=7.6 Hz, 1H), 4.43-4.39 (t, J=6.6 Hz, 2H), 3.16-3.13 (t, J=6.6 Hz, 2H), 2.19-2.17 (d, J=7.2 Hz, 2H), 2.15-2.08 (m, 1H), 0.92-0.90 (d, J=8 Hz, 2H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3-d): 172.0, 150.9, 139.4, 132.9, 130.1, 129.3, 125.7, 124.7, 124.2, 121.2, 120.7, 118.0, 116.0, 65.7, 46.4, 26.0, 25.0, 20.6 ppm. MS (ESI): m/z 474 [MH].sup., 510 [M+Cl].sup.

(142) 2-(1-(4-(3-(2-(trifluoromethyl)phenyl)ureido)phenyl)-1H-1,2,3-triazol-4-yl)ethyl 3-(benzo[d][1,3]dioxol-5-yl)acrylate (39). (Purification eluent: DCM-methanol 98:2). Yield 68% white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.12 (s, 1H), 8.02-8.00 (d, J=8 Hz, 1H), 7.60 (s, 1H), 7.58-7.52 (m, 7H), 7.34 (s, 1H), 7.22-7.18 (t, J=8 Hz, 1H), 7.00-6.97 (m, 2H), 6.80-6.78 (d, J=8 Hz), 6.28-6.24 (d, J=12 Hz, 1H), 5.99 (s, 2H), 4.55-4.52 (t, J=12.4 Hz, 2H), 3.22-3.25 (t, J=12.0 Hz, 2H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3-d): 167.7, 152.9, 118.6, 117.9, 145.8, 138.4, 133.4, 131.6, 129.7, 127.6, 126.4, 124.9, 121.3, 118.7, 116.2, 115.9, 108.4, 106.7, 103.1, 69.0, 24.2 ppm. MS (ESI): m/z 564.5 [MH].sup., 600.3 [M+Cl].sup.

Example 7

(143) ##STR00059##

(144) General Procedure for the Preparation of Fluorinated Compounds 40a-c:

(145) The opportune alcohol 31a, 31c, or 31d (400 mg, 1.38 mmol) was dissolved in 15 mL of CH.sub.2Cl.sub.2, and Deoxo-Fluor (533 L, 2.48 mmol), was added at 40 C. After stirring for 2 h at 40 C. the reaction mixture was warmed up to r.t. and stirred overnight. The solvent was removed at reduced pressure and the residue purified by flash chromatography on silica gel.

(146) 4-(fluoromethyl)-1-(4-nitrophenyl)-1H-1,2,3-triazole (40a): (Purification Eluent: DCM/MeOH 98:2) Yield: 67%, white solid .sup.1H NMR (400 MHz, ACETONE-d.sub.6): 8.94 (s, 1H), 8.49-8.46 (dd, J=8.8 Hz, 2H), 8.25-8.23 (dd, J=8.8 Hz, 2H), 5.64 (s, 1H), 5.52 (s, 1H) ppm. .sup.13C-NMR (100 MHz, ACETONE-d.sub.6): 147.50, 144.31, 141.34, 125.43, 123.38, 120.89, 76.00-74.39 (J.sub.CF=161.0 Hz) ppm.

(147) 4-(3-fluoropropyl)-1-(4-nitrophenyl)-1H-1,2,3-triazole (40 b): (Purification eluent: DCM-methanol 98:2). Yield 57% white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.40-8.38 (d, J=9.2 Hz, 2H), 7.97-7.95 (d, J=9.2 Hz, 2H), 7.90 (s, 1H), 4.61-4.59 (t, J=5.7 Hz, 1H), 4.49-4.46 (t, J=5.7 Hz, 1H), 2.98-2.94 (t, J=7.6 Hz, 2H), 2.23-2.10 (m, 2H) ppm. .sup.13C NMR (100 MHz CDCl.sub.3-d): 184.54, 147.08, 141.29, 125.53, 120.27, 119.09, 83.73-82.09 (J.sub.CF=164 Hz), 29.86-29.66 (J.sub.CF=20 Hz), 21.41 ppm.

(148) 4-(1-fluoro-2-methylpentyl)-1-(4-nitrophenyl)-1H-1,2,3-triazole (40c): (Purification eluent: DCM-methanol 98:2). Yield 67% white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.38-8.35 (d, J=8.8 Hz, 2H), 5.63-5.45 (m, 1H), 2.22-2.16 (m, 1H), 1.56-1.38 (m, 4H), 0.84-0.92 (m, 3H), 0.79-0.75 (t, J=7.2 Hz, 3H) ppm. MS (ESI) m/z 291 [MH].sup., 327 [M+Cl].sup..

(149) General Procedure for the Preparation of Compounds 41a-c

(150) The opportune triazole compound 40a 40b or 40c (100 mg, 0.34 mmol) was solubilized in 10 mL of anhydrous MeOH, and 10% Palladium on charcoal (30 mg) was added. The reaction mixture was stirred under Hydrogen atmosphere for 1 h, then the mixture was filtered off on a celite pad, the solvent evaporated at reduced pressure.

(151) 4-(4-(fluoromethyl)-1H-1,2,3-triazol-1-yl)aniline (41a): Yield 99% white solid. .sup.1H NMR (400 MHz, ACETONE-d.sub.6): 7.94 (s, 1H), 7.46-7.44 (dd, J=8.8 Hz, 2H), 6.77-6.75 (dd, J=8.4 Hz, 2H), 5.62 (s, 1H), 5.50 (s, 1H) ppm. MS (ESI) m/z 193 [M+H].sup.+, 215 [M+Na].sup.+.

(152) 4-(4-(3-fluoropropyl)-1H-1,2,3-triazol-1-yl)aniline (41b): Yield 99% white solid. .sup.1H NMR (400 MHz CDCl.sub.3-d): 8.51 (s, 1H), 7.84-7.82 (d, J=8.7 Hz, 2H), 7.36-7.34 (d, J=8.6 Hz, 2H), 7.90 (s, 1H), 5.91-4.89 (t, J=5.7 Hz, 1H), 4.99-4.96 (t, J=5.7 Hz, 1H), 2.98-2.94 (t, J=7.6 Hz, 2H), 2.23-2.10 (m, 2H) ppm. MS (ESI) m/z 221 [M+H].sup.+, 243 [M+Na].sup.+.

(153) 4-(4-(1-fluoro-2-methylpentyl)-1H-1,2,3-triazol-1-yl) aniline (41c): Yield 99% white solid. .sup.1H NMR (400 MHz CDCl.sub.3-d): 7.83 (s, 1H), 7.42-7.40 (d, J=8.4 Hz, 2H), 6.71-6.69 (d, J=8.4 Hz, 2H), 5.60-5.41 (m, 1H), 4.08 (s, 2H), 2.22-2.18 (m, 1H), 1.60-1.20 (m, 4H), 0.94-0.82 (m, 3H), 0.89-0.85 (t, J=7.2 Hz, 3H) ppm. MS (ESI) m/z 263 [M+H].sup.+, 285 [M+Na].sup.+.

(154) General Procedure for the Preparation of Compounds 42a 42b and 42c

(155) The opportune aniline compound 41-c (100 mg, 0.46 mmol) was added to a solution of the 0-(Trifluoromethyl)phenyl isocyanate 24 (85 L, 0.65 mmol) in anhydrous CH.sub.2Cl.sub.2 (10 mL) in one portion. The solution was stirred for 4 hours at r.t. under a nitrogen atmosphere. The solvent was removed, at reduced pressure and the residue purified by flash chromatography using the opportune eluent.

(156) 1-(4-(4-(fluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-(2-(trifluoromethyl)phenyl)urea (42a). (Purification Eluent: DCM/EA 95:5). Yield 79% .sup.1H NMR (400 MHz, ACETONE-d.sub.6): 9.09 (s, 1H), 8.64-8.63 (d, J=2.8 Hz, 1H), 8.15-8.13 (d, J=8.0 Hz, 1H), 7.82-7.64 (m, 5H), 7.31-7.27 (t, J=7.2 Hz, 1H), 5.60 (s, 1H), 5.44 (s, 1H) ppm .sup.13C-NMR (100 MHz, ACETONE-d.sub.6): 152.2, 140.56, 140.57, 132.95, 131.72, 125.90, 125.48, 123.78, 122.80, 121.13, 119.28, 76.16-74.53 (J.sub.CF=163.0 Hz) ppm MS (ESI) m/z 378 [MH].sup., 414 [M+Cl].sup..

(157) 1-(4-(4-(3-fluoropropyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-(2 (trifluoromethyl)phenyl) urea. (42b). Yield 87% white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.80 s (1H), 7.93 (s, 1H), 7.75-7.73 (d, 1H), 7.71 (s, 1H), 7.51-7.49 (m, 3H), 7.42-7.39 (m, 3H), 7.11-7.09 (t, 1H), 5.91-4.89 (m, J=5.7 Hz, 1H), 4.99-4.96 (m, J=5.7 Hz, 1H), 2.98-2.94 (t, J=7.6 Hz, 2H), 2.23-2.10 (m, 2H) ppm. MS (ESI) m/z 408 [M+H].sup.+, 430 [M+Na].sup.+. .sup.13C NMR (100 MHz CDCl.sub.3-d): 152.91, 139.44, 132.83, 129.62, 126.77, 121.88, 120.43, 119.13, 115.88, 83.73-82.09 (J.sub.CF=164 Hz), 32.71-32.51 (J.sub.C-F=20 Hz), 27.31 ppm.

(158) 1-(4-(4-(1-fluoro-2-methylpentyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-(2-(trifluoromethyl) phenyl) urea (42c): Yield 99% white solid. .sup.1H NMR (400 MHz CDCl.sub.3-d): 8.83 s (1H), 7.90 (s, 1H), 7.79-7.77 (d, 1H), 7.70 (s, 1H), 7.49-7.47 (m, 3H), 7.43-7.40 (m, 3H), 7.12-7.10 (t, 1H), 5.61-5.42 (m, 1H), 2.32-2.10 (m, 1H), 1.42-1.40 (m, 2H), 1.29-1.21 (m, 2H), 0-98-0.86 (m, 6H) ppm. .sup.13C NMR (100 MHz CDCl.sub.3-d): 153.85, 147.65, 139.63, 135.31, 132.49, 131.75, 127.90, 126.82, 126.14, 125.17, 124.81, 122.84, 122.54, 121.20, 120.34, 92.81-91.18 (J.sub.C-F=164 Hz), 90.72-90.49 (J.sub.C-F=23 Hz), 37.64-37.44 (J.sub.C-F=20 Hz); 34.45, 33.55, 19.98, 14.07, 13.80 ppm. MS (ESI) m/z 450.1 [M+H].sup.+, 472.1[M+Na].sup.+.

Example 8

(159) ##STR00060##

(160) 5-(4-nitrophenyl)-2H-tetrazole (44). A mixture of 4-nitrobenzonitrile (600 mg, 4.05 mmol) sodium azide (790 mg, 12.15 mmol) ammonium chloride (867 mg, 16.20 mmol) and DMF (5 mL) was heated at 120 C. for 12 hr. Then the reaction was allowed to cool to r.t., water was added with continuous stirring. The mixture was then acidified to pH 2 with HCl 6N. The reaction mixture was extracted with EtOAc (320 mL) and dried over Na.sub.2SO.sub.4, and the solvent was removed under reduced pressure, to give a yellow residue that was crystallized from Ethanol Yield 80% white solid .sup.1H NMR (MeOD-d.sub.4): 8.40-8.38 (d, 2H, J=7.2 Hz), 8.28-8.28 (d, 2H, J=8 Hz) ppm. .sup.13C NMR (MeOD-d.sub.4): 156.72, 149.46, 131.32, 128.18, 124.07 ppm. MS: m/z 189.9 [MH].sup.

(161) 2-butyl-5-(4-nitrophenyl)-2H-tetrazole (45). A suspension of 44 (200 mg, 1.05 mmol), K.sub.2CO.sub.3 (174 mg, 1.26 mmol) and n-butyliodide (144 L, 1.26 mmol), in Acetonitrile was refluxed for 4 h. After that time, the reaction mixture was concentrated in vacuo, water was added and the residue was extracted with AcOEt (325 mL), washed with brine, and dried over Na.sub.2SO.sub.4. The resulting residue was purified by flash chromatography on silica gel (PE-DCM 1:8). Yield 82%, yellow solid. .sup.1H NMR (400 MHz CDCl.sub.3-d): 8.26 (m, 4H), 4.67-4.63 (t, J=7.6 Hz, 2H), 2.03-1.98 (quint, J=6.8 Hz, 2H), 1.40-1.34 (sx. J=7.2 Hz, 2H) 0.95-0.92 (t, J=7.2 Hz, 3H) ppm. .sup.13C NMR (100 MHz CDCl.sub.3-d): 163.05, 148.74, 133.42, 127.53, 124.10, 53.20, 31.22, 19.57, 13.30 ppm. MS: m/z 220 [M+H]+

(162) 2-(ethoxymethyl)-5-(4-nitrophenyl)-2H-tetrazole (46). A suspension of 44 (50 mg, 0.26 mmol), K.sub.2CO.sub.3 (43 mg, 0.31 mmol) and chloromethylethylether (28 L, 0.31 mmol), in Acetonitrile was refluxed for 12 h. After that time, the reaction mixture was concentrated in vacuo, water was added and the residue was extracted with AcOEt (325 mL), washed with brine, and dried over Na.sub.2SO.sub.4. The resulting residue was purified by flash chromatography on silica gel (PE-DCM 1:7). Yield 66%, yellow solid. A suspension of .sup.1H NMR (Acetone d-.sub.6): 8.42-8.34 (m, 4H), 6.05 (s, 2H), 3.79-3.69 (m, 2H), 1.19-1.09 (m, 3H) ppm; .sup.13C NMR (Acetone d-.sub.6): 163.80, 149.22, 133.18, 127.83, 123.94, 81.90, 66.35, 14.34 ppm.

(163) 4-(2-butyl-2H-tetrazol-5-yl)aniline (47). Compound 45 (100 mg, 0.40 mmol) was solubilized in 30 mL of anhydrous MeOH, and 10% Palladium on charcoal (5 mg) was added. The reaction mixture was stirred under Hydrogen atmosphere for 1 h, then the mixture was filtered off on a celite pad, the solvent evaporated at reduced pressure. Yield 99% .sup.1H NMR (400 MHz CDCl.sub.3-d): 7.90-7.88 (d, J=8.0 Hz, 2H), 6.71-6.69 (d, J=8.0 Hz, 2H), 4.57-4.53 (t, J=7.6 Hz, 2H), 4.03 (s, 2H), 2.00-1.92, (quint, J=8.1 Hz, 2H), 1.38-1.23 (sx, J=8.0 Hz, 2H), 0.93-0.89 (t, 8.0 Hz, 3H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3-d): 165.62, 148.77, 128.04, 117.56, 114.87, 113.12, 52.69, 31.38, 19.56, 12.17 ppm MS (ESI): m/z 218 [M+H]+, 239.9 [M+Na].sup.+.

(164) 4-(2-(ethoxymethyl)-2H-tetrazol-5-yl)aniline (48). Compound 46 (150 mg, 0.60 mmol) was solubilized in 30 mL of anhydrous MeOH, and 10% Palladium on charcoal (5 mg) was added. The reaction mixture was stirred under Hydrogen atmosphere for 1 h, then the mixture was filtered off on a celite pad, the solvent evaporated at reduced pressure. Yield 99%.sup.1H NMR (400 MHz CDCl.sub.3-d): 7.97-7.95 (d, 2H, J=7.2 Hz), 6.75-6.73 (d, 2H, J=7.2 Hz), 5.870 (s, 2H), 3.69-68 (m, 2H), 1.241 (s, 3H) ppm. MS: m/z 220 [M+H]+

(165) 1-(4-(2-butyl-2H-tetrazol-5-yl)phenyl)-3-(o-tolyl)urea (49). Compound 47 (0.10 mmol) was added to a solution of o-tolyl isocyanate (0.15 mmol) in anhydrous MeOH (10 mL) in one portion. The solution was stirred for 9 hours at r.t. under a nitrogen atmosphere. The solvent was removed at reduced pressure and the residue purified on silica to furnish the final product as white solid. (DCM-MeOH 98:2). Yield 73% .sup.1H NMR (Acetone d-.sub.6): 8.60 (s, 1H), 8.03-8.01 (d, J=8 Hz, 2H), 7.92-7.90 (d, J=8.0 Hz, 2H), 7.55 (s, 1H), 7.18-7.14 (m, 2H), 6.99-6.95 (t, J=7.6 Hz, 1H), 4.71-4.67 (t, J=, 2H), 2.27 (s, 1H), 2.03-1.98 (m, 2H), 1.43-1.34 (sx, J=7.6 Hz, 2H), 0.97-0.94 (t, J=7.4 Hz, 3H) ppm. .sup.13C NMR (Acetone): 164.91, 152.54, 142.16, 137.33, 130.35, 128.48, 127.64, 126.40, 123.44, 122.20, 121.37, 118.75, 52.47, 31.09, 19.34, 17.17, 12.73 ppm. MS: m/z 351 [M+H]+

(166) 1-(4-(2-(ethoxymethyl)-2H-tetrazol-5-yl)phenyl)-3-(o-tolyl)urea (50). Compound 48 (0.10 mmol) was added to a solution of o-tolyl isocyanate (0.15 mmol) in anhydrous MeOH (10 mL) in one portion. The solution was stirred for 9 hours at r.t. under a nitrogen atmosphere. The solvent was removed at reduced pressure and the residue purified on silica to furnish the final product as white solid. (DCM-MeOH 98:2). Yield 62% .sup.1H NMR (400 MHz CDCl.sub.3-d): 8.06-8.04 (d, 2H, J=8 Hz), 7.65-7.62 (m, 3H), 7.21-7.15 (m, 2H), 7.05-7.01 (t, 1H, J=7.6 Hz), 5.95 (s, 2H), 3.74-3.69 (q, 2H), 2.30 (s, 3H), 1.20-1.17 (t, 3H, J=6.8 Hz) ppm. .sup.13C NMR (100 MHz CDCl.sub.3-d): 142.06, 136.14, 130.47, 127.51, 126.33, 124.73, 123.05, 120.95, 118.61, 80.93, 66.18, 16.61, 13.32 ppm. MS: m/z 375 [M+Na]+

(167) 1-(4-(2-butyl-2H-tetrazol-5-yl)phenyl)-3-(2-(trifluoromethyl)phenyl)urea (51). Compound 47 (0.10 mmol) was added to a solution of o-tolyl isocyanate (0.15 mmol) in anhydrous MeOH (10 mL) in one portion. The solution was stirred for 9 hours at r.t. under a nitrogen atmosphere. The solvent was removed at reduced pressure and the residue purified on silica to furnish the final product as white solid. (DCM-MeOH 98:2). Yield 70%, white solid. .sup.1H NMR (400 MHz CDCl.sub.3-d): 7.93-7.91 (d, J=8 Hz, 2H), 7.82-7.80 (d, J=8.0 Hz, 1H), 7.48-7.39 (m, 2H), 7.36-7.34 (d, J=7.2 Hz, 2H), 7.09-7.05 (t, J=7.2 Hz, 1H), 4.60-4.57 (t, J=6.8 Hz, 2H), 2.01-1.97 (m, 2H), 1.39-1.33 (m, 2H), 0.95-0.91 (t, J=7.2 Hz, 3H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3-d): 153.54, 140.20, 135.38, 132.54, 127.60, 126.29, 126.11, 125.23, 124.54, 122.43, 122.01, 120.07, 52.96, 31.27, 19.60, 13.34 ppm MS (ESI) m/z 405 [M+H].sup.+, 428 [M+Na].sup.+.

(168) 1-(4-(2-butyl-2H-tetrazol-5-yl)phenyl)-3-(4-methylpyridin-3-yl)urea (52): A solution of 4-methylpyridin-3-amine (41 mg, 0.3835 mmol) and DMAP (19 mg, 0.1534 mmol) in 5 mL of CH.sub.2Cl.sub.2 was added dropwise to an ice cold solution of triphosgene in CH.sub.2Cl.sub.2, during 30 min., then aniline 47 was added in one portion, and the reaction mixture was stirred at rt for 12 h. After this time, 2M HCl was added and the mixture was extracted with CH.sub.2Cl.sub.2 (320 mL). The organic layers were collected, washed with Brine and dried over Na.sub.2SO.sub.4. The crude was purified by flash chromatography on silica gel (CH.sub.2Cl.sub.2-MeOH 98:2). Yield 70%. .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.87 (s, 1H), 8.15 (d, 1H), 8.03-8.61 (d, J=8.0 Hz, 2H), 7.63-7.61 (d, J=8.0 Hz, 2H), 7.30-7.29 (d, J=4 Hz, 1H), 4.71-4.67 (t, J=7.8 Hz, 2H), 2.35 (s, 3H), 2.06-1.99 (q, J=9.3 Hz, 2H), 1.42-1.36, (q, 2H), 1.00-0.97 (t, J=8.0 Hz, 3H) ppm. .sup.13C NMR (MeOD-d.sub.4): 164.69, 153.57, 143.82, 143.19, 141.39, 140.12, 134.50, 127.09, 125.50, 121.37, 118.72, 52.64, 31.03, 19.38, 16.20, 12.29 ppm. MS (ESI) m/z 353.2 [M+H].sup.+, 375.2 [M+Na].sup.+.

Example 9

(169) ##STR00061##

(170) Urea derivatives 55a-g are reported in Table 1

(171) TABLE-US-00002 TABLE 1 List of urea derivatives 55a-r embedded image Aromatic Iso- Entry amine R.sub.1 cyanate Amine R.sub.2 Compound 1 53a 54a 17b 2 53b 54b 17b 3 53c 54c 17b 0 4 53d 54d 17b 5 53e 54e 17e 6 53f 54f 17b 0 7 53g 54g 17b 8 53h 54h 19a 9 53i 54i 19a 10 53a 0 54a 19a 11 53b 54b 19a 12 53b 54b 55n 13 53b 54b 19e 00 embedded image 01 14 53l 02 53l 19a 03 04 15 53l 05 54l 19a 06 07

(172) General Procedure for the Preparation of 55a-q:

(173) A solution of the opportune aromatic amine (41 mg, 0.3835 mmol) and DMAP (19 mg, 0.1534 mmol) in 5 mL of CH.sub.2Cl.sub.2 was added dropwise to an ice cold solution of triphosgene in CH.sub.2Cl.sub.2, during 30 min., then the opportune aniline 17a-c was added in one portion, and the reaction mixture was stirred at r.t. for 12 h. After this time, 2M HCl was added and the mixture was extracted with CH.sub.2Cl.sub.2 (320 mL). The organic layers were collected, washed with Brine and dried over Na.sub.2SO.sub.4. The crude was purified by flash chromatography on silica gel using the opportune eluent.

(174) 1-(2-fluorophenyl)-3-(4-(4-isopentyl-1H-1,2,3-triazol-1-yl)phenyl)urea (55a): (Purification eluent: DCM/MeOH 98:2). Yield 68%, white solid. .sup.1HNMR (400 MHz, MeOD-d.sub.4): 8.07-8.03 (t, J=8.0 Hz, 1H), 7.64 (s, 1H), 7.56-7.50 (m, 4H), 7.08-6.75 (m, 3H) 2.76-2.72 (t, J=8.0 Hz, 2H), 1.64-1.54 (m, 3H), 0.92-0.90 (d, 6H) ppm. .sup.13CNMR (MeOD-d.sub.4): 154.32, 152.91, 139.45, 132.87, 129.94, 129.06, 123.88, 121.63, 119.11, 115.72, 38.37, 27.62, 23.41, 22.29 ppm. MS (ESI) m/z 366 [MH].sup., 402 [M+Cl].sup..

(175) 1-(3-fluorophenyl)-3-(4-(4-isopentyl-1H-1,2,3-triazol-1-yl)phenyl)urea (55b): (Purification eluent: DCM/MeOH 98:2). Yield 70%, white solid. .sup.1HNMR (400 MHz, MeOD-d.sub.4): 7.74-7.73 (m, 1H), 7.54-7.53 (m, 4H), 7.34-7.32 (m, 1H), 7.25-7.24 (m, 1H), 7.18-7.16 (m 1H), 7.07-7.06 (m, 1H), 6.68-6.65 (t, J=8.0 Hz, 1H), 2.75-2.73 (t, J=8.0 Hz, 2H), 1.62-1.58 (m, 3H), 0.92-0.90 (d, 6H) ppm. .sup.13CNMR (MeOD-d.sub.4): 164.10, 153.91, 139.83, 137.51, 133.81, 133.49, 131.51, 129.82, 121.61, 119.17, 117.24, 116.51, 42.71, 29.12, 27.21, 23.27 ppm. MS (ESI) m/z 366 [MH].sup., 402 [M+Cl].sup..

(176) 1-(4-fluorophenyl)-3-(4-(4-isopentyl-1H-1,2,3-triazol-1-yl)phenyl)urea (55c): (Purification eluent: PE/EA 7:3). Yield 63%, white solid. .sup.1H NMR (400 MHz, Acetone-d.sub.6): 8.48 (s, 1H), 8.34 (s, 1H), 8.15 (s, 1H), 7.71-7.66 (m, 4H), 7.53-7.49 (m, 2H), 7.02-6.97 (m, 2H), 2.72-2.68 (m, 2H), 1.60-1.53 (m, 3H), 0.90-0.88 (d, J=8.0 Hz, 6H) ppm. .sup.13C-NMR (100 MHz, Acetone-d.sub.6): 159.71, 152.58, 140.25, 136.40, 131.97, 130.07, 124.70, 120.60, 119.06, 118.60, 115.20, 38.53, 27.36, 23.31, 21.58 ppm. MS (ESI) m/z 366 [MH].sup., 402 [M+Cl].sup..

(177) 1-(3-chloro-2-methylphenyl)-3-(4-(4-isopentyl-1H-1,2,3-triazol-1-yl)phenyl) urea (55d): (Purification eluent: DCM/MeOH 98:2). Yield 80%, white solid. .sup.1HNMR (MeOD-d.sub.4): 7.89 (s, 1H), 7.64-7.57 (m, 4H), 7.08-7.06 (d, J=8.0 Hz, 1H), 6.95-6.93 (d, J=8.0 Hz, 1H), 2.77-2.73 (t, J=7.2 Hz, 2H), 2.23 (s, 3H), 1.60-1.56 (m, 3H), 0.94-0.93 (d, J=6.0 Hz, 6H) ppm. .sup.13C NMR (100 MHz CDCl.sub.3-d): 153.48, 149.08, 139.85, 137.69, 131.73, 131.14, 126.60, 123.47, 121.61, 121.16, 119.74 ppm. MS (ESI): m/z 396 [MH].sup.

(178) 1-(4-(4-(ethoxymethyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-(5-isopropyl-2-methyl phenyl) urea (55e): (Purification eluent: DCM/MeOH 98:2). Yield 70%, white solid. .sup.1HNMR (400 MHz CDCl.sub.3-d): 8.39 (s, 1H), 7.85 (s, 1H), 7.46-7.37 (m, 4H), 7.02-7.00 (d, J=8.0 Hz, 1H), 6.89-6.87 (d, J=8.0 Hz, 1H), 4.66 (s, 2H), 3.63-3.58 (q, J=7.8 Hz, 2H), 2.81, 2.75 (m, 1H), 2.10 (s, 1H), 1.23-1.20 (t, J=6.8 Hz, 3H), 1.16-1.14 (d, J=8.0 Hz, 6H) ppm. .sup.13CNMR (100 MHz CDCl.sub.3-d): 154.22, 147.65, 145.95, 139.97, 135.57, 131.52, 131.52, 130.54, 128.69, 123.47, 122.80, 121.22, 120.96, 120.01, 66.40, 63.90, 33.66, 23.92, 17.42, 15.09 ppm. MS (ESI) m/z 394.1 [M+H].sup.+, 416.1 [M+Na].sup.+.

(179) 1-(4-(4-isopentyl-1H-1,2,3-triazol-1-yl)phenyl)-3-(isoquinolin-5-yl)urea (55f): (Purification eluent: DCM/MeOH 98:2). Yield 63%, white solid. .sup.1HNMR (400 MHz CDCl.sub.3-d): 9.22 (s, 1H), 8.46 (m, 1H), 8.22-8.20 (m, 2H), 7.96 (s, 1H), 7.89-7.87 (d, J=8.0 Hz, 1H), 7.73-7.67 (m, 5H), 2.78-2.74 (t, J=7.2 Hz, 2H), 1.61-1.57 (m, 3H), 0.93-0.92 (d, J=6.0 Hz, 6H) ppm. .sup.13CNMR (100 MHz CDCl.sub.3-d): 152.81, 142.11, 140.21, 139.45, 132.84, 129.87, 129.01, 124.88, 121.62, 119.11, 115.75, 114.81, 112.42, 42.66, 30.11, 27.76, 23.21 ppm. MS (ESI) m/z 399.1 [MH].sup., 435.1 [M+Cl].sup.

(180) 1-(1-chloro-3-methylisoquinolin-4-yl)-3-(4-(4-isopentyl-1H-1,2,3-triazol-1-yl)phenyl)urea (55g): (Purification eluent: DCM/MeOH 98:2). Yield 60%, white solid. .sup.1HNMR (400 MHz, MeOD-d.sub.4): 8.34-8.32 (d, J=8.0 Hz, 1H), 8.21 (s, 1H), 8.08-8.06 (d, J=8.0 Hz, 1H), 7.89-7.84 (t, J=8.0 Hz, 1H), 7.74, 7.20 (m, 3H), 7.67-7.65 (d, J=8.0 Hz, 2H), 2.79-2.75 (t, J=7.2 Hz, 2H), 2.62 (s, 3H), 1.64-1.61 (m, 3H), 0.93-0.92 (d, J=6.0 Hz, 6H) ppm. .sup.13CNMR (100 MHz CDCl.sub.3-d): 151.88, 148.47, 139.86, 137.05, 134.65, 132.12, 131.84, 128.04, 126.23, 122.63, 121.02, 119.62, 119.1, 114.81, 112.41, 38.27, 29.45, 27.45, 22.84, 21.44, 19.03 ppm. MS (ESI) m/z 447.1 [MH].sup., 483.1 [M+Cl].sup..

(181) 1-(4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl)-3-(5-(cyclopentyloxy)-2-methylphenyl)urea (55h)): (Purification eluent: DCM/MeOH 98:2). Yield 76%, white solid. .sup.1HNMR (400 MHz, Acetone-d6): 8.64 (s, 1H), 8.17 (s, 1H), 7.74-7.65 (m, 5H), 7.48 (s, 1H), 7.01-7.99 (d, J=3.9 Hz, 1H), 6.51-6.48 (dd, J=5.6 Hz, J=5.6 Hz, 0.2 Hz, 1H), 4.75-4.74 (m, 1H), 2.75-2.70 (t, J=7.8 Hz, 2H), 2.16 (s, 3H), 1.91-1.88 (m, 2H), 1.77-1.63 (m, 8H), 1.42-1.38 (m, 2H), 1.01-1.98 (t, J=8 Hz, 3H). .sup.13CNMR (100 MHz Acetone-d6): 154.56, 153.62, 136.75, 136.64, 135.76, 128.05, 125.09, 123.49, 123.07, 123.07, 122.17, 122.17, 109.66, 106.38, 82.15, 33.39, 33.39, 29.99, 27.92, 24.10, 24.10, 22.18, 17.35, 14.02.

(182) 1-(4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl)-3-(5-(methoxymethoxy)-2-methylphenyl)urea (55i): (Purification eluent: DCM/MeOH 98:2). Yield 70%, white solid. .sup.1HNMR (400 MHz, Acetone-d6): =8.63 (s, 1H), 8.16 (s, 1H), 7.76-7.60 (m, 5H), 7.51 (s, 1H), 7.03 (d, J=8.3, 2H), 6.64 (dd, J=8.3, 2.6, 2H), 5.12 (s, 2H), 3.39 (s, 3H), 2.71 (t, J=7.6, 2H), 2.17 (s, 3H), 1.66 (m, 2H), 1.43-1.34 (m, 2H), 0.93-0.89 (t, J=7.8 Hz, 3H) ppm. .sup.13CNMR (100 MHz Acetone-d6): 156.07, 152.45, 148.35, 140.15, 138.13, 131.93, 131.11, 129.97, 120.57, 119.10, 118.18, 111.30, 109.96, 109.81, 94.35 55.45, 29.99, 27.92, 22.18, 17.35, 14.02 ppm. MS (ESI) m/z 408.1 [MH].sup., 444.1 [M+Cl].sup..

(183) 1-(4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl)-3-(3-fluorophenyl)urea (55l): (Purification eluent: DCM/MeOH 98:2). Yield 80%, white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d) 7.34 (s, 2H), 7.11-6.93 (m, 4H), 6.66 (s, 2H), 6.48 (s, 2H), 6.25 (d, J=7.5 Hz, 4H), 6.14-6.03 (m, 4H), 5.94 (s, 2H), 5.73 (s, 2H), 2.03-1.98 (m, 4H), 1.00-0.95 (m, 3H), 0.69-0.64 (m, 3H), 0.28-0.22 (m, 6H). .sup.13C NMR (100 MHz, CDCl.sub.3-d) : 160.36, 154.56, 154.07, 140.81, 136.75, 135.76, 129.04, 125.09, 123.07, 123.07, 122.17, 122.17, 117.53, 111.81, 110.08, 29.99, 27.92, 22.18, 14.02. ppm. MS (ESI) m/z 352 [MH].sup., 388 [M+Cl].sup..

(184) 1-(4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl)-3-(3-fluorophenyl)urea (55m): (Purification eluent: DCM/MeOH 98:2). Yield 80%, white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d) : 7.78 (s, 1H), 7.59 (m, 4H), 7.37 (d, J=10.6, 1H), 7.22 (dd, J=15.4, 7.2, 1H), 7.08 (d, J=8.0, 1H), 6.71 (t, J=8.2, 1H), 2.77 (t, J=7.6, 2H), 1.77-1.54 (m, 2H), 1.47-1.17 (m, 2H), 0.96-0.93 (t, J=7 Hz 3H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3-d) 160.36, 154.56, 154.07, 140.81, 136.75, 135.76, 129.04, 125.09, 123.07, 123.07, 122.17, 122.17, 117.53, 111.81, 110.08, 29.99, 27.92, 22.18, 14.02 ppm. MS (ESI) m/z 352 [MH].sup., 388 [M+Cl].sup..

(185) 1-(3-fluorophenyl)-3-(4-(4-(3-oxobutyl)-1H-1,2,3-triazol-1-yl)phenyl)urea (55n): (Purification eluent: DCM/MeOH 98:2). Yield 75%, white solid. .sup.1H NMR (400 MHz, Acetone-d.sub.6) 8.54-8.51 (m, 2H), 8.15 (s, 1H), 7.81-7.56 (m, 4H), 7.58-7.55 (d, J=12 Hz, 1H), 7.22 (m, 1H), 7.28-7.26 (d, J=8 Hz, 1H), 6.73-6.69 (t, J=7.3 Hz, 1H), 2.95-2.88 (m, 4H), 2.12 (s, 3H), ppm. .sup.13C NMR (100 MHz, Acetone-d6) 206.98, 160.36, 154.07, 153.06, 140.81, 136.75, 135.76, 129.04, 123.07, 123.07, 122.17, 122.17, 121.34, 117.53, 111.81, 110.08, 41.35, 28.57, 20.36. ppm. MS (ESI) m/z 366 [MH].sup., 402 [M+Cl].sup..

(186) 1-(4-(4-(ethoxymethyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-(3-fluorophenyl)urea (55o): (Purification eluent: DCM/MeOH 98:2). Yield 72%, white solid. .sup.1H NMR (400 MHz, Acetone-d6) : 8.46-8.38 (m, 3H), 7.76-7.70 (m, 4H), 7.58-7.55 (d, J=11 Hz, 1H), 7.27-7.24 (t, J=6 Hz, 1H), 7.17-7.15 (d, J=7 Hz, 1H), 6.74-6.71 (t, J=7 Hz, 1H), 4.59 (s, 1H), 3.57-3.52 (q, J=6.7 Hz, 2H), 1.16-1.13 (t, J=6.6 Hz, 3H) ppm. .sup.13C NMR (100 MHz, Acetone d.sub.6) 164.26, 161.86, 152.22, 145.85, 140.05, 131.95, 130.14, 121.06, 120.89, 119.35, 114.13, 108.63, 108.42, 105.64, 105.38, 65.30, 63.54, 14.55, 43.88. ppm. MS (ESI) m/z 354 [MH].sup., 390 [M+Cl].sup..

(187) 1-(4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl)-3-(2-methyl-5-(3-oxobutyl)phenyl)urea (55p): (Purification eluent: DCM/MeOH 98:2). Yield 72%, white solid. .sup.1H NMR (400 MHz, MeOD-d4) 8.18 (s, 1H), 7.70 (d, J=9.0 Hz, 2H), 7.62 (d, J=8.9 Hz, 2H), 7.49 (s, 1H), 7.08 (d, J=7.7 Hz, 1H), 6.87 (d, J=6.7 Hz, 1H), 2.79-2.73 (m, 4H), 2.23 (s, 3H), 2.11 (s, 3H), 1.68 (m, 2H), 1.47-1.36 (m, 2H), 0.95 (t, J=7.3 Hz, 3H) ppm. .sup.13C NMR (100 MHz MeOD-d4) 208.15, 154.56, 139.69, 138.44, 136.75, 135.76, 130.90, 128.16, 125.90, 125.09, 123.54, 123.07, 123.07, 122.17, 122.17, 40.44, 31.99, 29.99, 28.57, 27.92, 22.18, 17.35, 14.02 ppm. MS (ESI) m/z 417.9 [MH].sup., 453.8 [M+Cl].sup..

(188) 1-(4-(4-butyl-1H-1,2,3-triazol-1-yl)phenyl)-3-(5-fluoropyridin-3-yl)urea (55q): (Purification eluent: DCM/MeOH 99:2). Yield 67%, white solid. .sup.1H NMR (400 MHz, MeOD-d.sub.4) 9.30 (d, J=1.4 Hz, 1H), 8.10-7.99 (m, 2H), 7.92 (d, J=7.4 Hz, 2H), 7.66-7.57 (m, 3H), 6.52 (d, J=4.8 Hz, 2H), 2.74 (t, J=8.0 Hz, 2H), 1.71 (p, J=7.9 Hz, 2H), 1.48-1.34 (m, 2H), 1.00 (t, J=6.6 Hz, 3H). ppm. .sup.13C NMR (100 MHz MeOD-d.sub.4) 159.43, 154.56, 154.07, 139.94, 136.75, 135.76, 134.14, 133.93, 125.09, 123.07, 123.07, 122.17, 122.17, 115.14, 29.99, 27.92, 22.18, 14.02 ppm. MS (ESI) m/z 353 [MH].sup..

Example 10

(189) ##STR00108## ##STR00109##

(190) The list of synthesized sulfonamide derivatives is reported in Table 2.

(191) TABLE-US-00003 TABLE 2 List of synthesized sulfonamide derivatives En- Chlo- Aromatic Nitro Amino- Al- try ryde amine R.sub.1 Cmpd. Cmpd. Azide kyne R.sub.2 Compound 1 56a 57a o-OH-Phe 58a 60a 62a 30a -Butyl 0 embedded image 2 56b 57a o-OH-Phe 59a 61a 63a 30a -Butyl 3 56a 57b p-MeO-Phe 58b 60b 62b 30a -Butyl 4 56a 57c o-Me-Phe 58c 60c 62c 30a -Butyl 5 56a 57d o-CF.sub.3-Phe 58d 60d 62d 30a -Butyl 6 56a 57d o-CF.sub.3-Phe 58d 60d 62d 30f CH.sub.2OCH.sub.2CH.sub.3 7 56a 57d o-CF.sub.3-Phe 58d 60d 62d 30b Isopentyl embedded image 8 56b 57c o-CF.sub.3-Phe 59c 61c 63c 30a -Butyl 9 56a 57e 58e 60e 62e 30a -Butyl 10 56a 57e 0 58e 60e 62e 30f CH.sub.2OCH.sub.2CH.sub.3

(192) General Procedure for the Preparation of Sulfonamides 58-59a-e

(193) To a stirred solution of the opportune aromatic amine (1 eq.) in 5 mL of anhydrous pyridine, was added the corresponding sulphonyl chloride (1.1 eq) at 0 C. The corresponding solution was stirred at r.t. under nitrogen atmosphere, for 5 h. After completion of the reaction the mixture was acidified with 20 mL of 2N HCl, the aqueous phase was extracted with several times and the combined organic phases were dried (Na.sub.2SO.sub.4) and concentrated.

(194) N-(2-hydroxy)-3-nitro-phenylbenzenesulfonamide (58a). The residue was purified by flash chromatography on silica gel (Hexane-AcOEt 3:1). Yield 84%. .sup.1H NMR (Acetone): 8.70 (s, 1H), 8.59, (s, 1H), 8.45-8.42 (d, J=12 Hz, 1H), 8.13-8.12 (d, J=4.3 Hz, 1H), 7.83-7.79 (t, J=8.1 Hz, 1H), 7.36-7.34 (d, J=8.2 Hz, 1H), 7.02-6.98 (t, J=8 Hz, 1H), 6.83-6.76 (m, 2H). MS (ESI): m/z 292.8 [MH].sup..

(195) N-(2-hydroxy)-4-nitro-phenylbenzenesulfonamide (59a). .sup.1H NMR (MeOD-d.sub.4): 8.25-8.22 (dd, 2H, J=8.4 Hz), 7.93-7.91 (dd, 2H, J=8.4 Hz), 7.33-7.31 (d, 1H), 6.97-6.94 (t, J=7.6 Hz, 1H), 6.76-6.73 (t, J=7.6 Hz, H), 6.66-6.64 (d, J=8 Hz, 1H) ppm. .sup.13C NMR (MeOD-d.sub.4): 150.36, 150.06, 128.56, 127.06, 125.55, 123.55, 119.29, 115.53 ppm. MS: m/z 292.8 [MH].sup.

(196) N-(4-methoxy)-3-nitro-phenylbenzenesulfonamide (58b). The residue was purified by flash chromatography on silica gel (Hexane-AcOEt 3:1). Yield 84%. .sup.1H NMR (400 MHz CDCl.sub.3-d): 8.57 (s, 1H), 8.39-8.37 (d, J=8 Hz, 1H), 7.97-7.95 (d, J=8.0 Hz, 1H), 7.65-7.61 (t, J=7.7 Hz, 1H), 6.99-6.97 (dd, J=8.1 Hz, 2H), 6.78-6.76 (dd, J=8.1 Hz, 2H), 6.69 (s, 1H), 3.75 (s, 3H) ppm. MS (ESI): m/z 309 [M+H].sup.+.

(197) N-(2-trifluoromethyl)-3-nitro-phenylbenzenesulfonamide (58c). The residue was purified by flash chromatography on silica gel (Hexane-AcOEt 3:1). Yield 84%. .sup.1H NMR (400 MHz CDCl.sub.3-d): 8.56 (s, 1H), 8.40-8.38 (d, J=8.4 Hz, 1H), 8.06-8.04 (d, J=8 Hz, 1H), 7.86-7.84 (d, J=8 Hz, 1H), 7.69-7.64 (t, J=8 Hz, 1H), 7.61-7.57 (t, J=7.8 Hz, 1H), 7.52-7.50 (d, J=8.0 Hz, 1H), 7.31-7.27 (t, J=8.1 Hz, 1H), 6.86 (s, 1H). .sup.13C NMR (100 MHz CDCl.sub.3-d): 148.16, 140.78, 133.53, 133.17, 132.66, 130.53, 127.79, 126.83, 126.78, 126.31, 124.91, 122.51, 122.02 MS (ESI): m/z 286.8 [M+Na].sup.+.

(198) N-(2-trifluoromethyl)-4-nitro-phenylbenzenesulfonamide (59c) The residue was purified by flash chromatography on silica gel (Hexane-AcOEt 3:1). Yield 84%. .sup.1H NMR (400 MHz CDCl.sub.3-d): 8.27-8.25 (d, J=8.0 Hz, 1H), 7.91-7.89 (d, J=8.0 Hz, 1H), 7.87-7.85 (d, J=8.0 Hz, 2H), 7.61-7.57 (t, J=8.0 Hz, 1H), 7.53-7.51 (d, J=8.0 Hz, 1H), 7.32-7.25 (t, J=8 Hz, 1H), 6.91 (s, 1H) ppm. .sup.13C NMR (100 MHz CDCl.sub.3-d): 150.80, 144.33, 139.34, 133.61, 128.99, 127.14, 126.03, 124.00 ppm.

(199) N-(2-methyl)-3-nitro-phenylenzenesulfonamide (58d) The residue was purified by flash chromatography on silica gel (Hexane-AcOEt 3:1). Yield 84%. .sup.1H NMR (Acetone): 8.49-8.47 (m, 2H), 8.09-8.07 (d, J=8 Hz, 1H), 7.87-7.83 (t, J=8 Hz, 1H), 7.17-7.10 (m, 4H) ppm.

(200) N-(isoquinolin-6-yl)-3-nitrobenzenesulfonamide (58e): (Purification eluent: PE-AcOEt: 4-1) Yield 67%. .sup.1H NMR (DMSO d-.sub.6): 9.56 (s, 1H), 8.52-8.50 (d, J=6.4 Hz, 1H), 8.44-8.41 (m, 2H), 8.21-8.19 (d, J=8.0 Hz, 1H), 8.07-8.05 (d, J=6.4 Hz, 1H), 8.01-7.99 (d, J=7.6 Hz, 1H), 7.79-7.70 (m, 2H), 7.55-7.53 (d, J=7.7 Hz, 1H) ppm.

(201) N-(2-methyl)-4-nitro-phenylenzenesulfonamide (59d) The residue was purified by flash chromatography on silica gel (Hexane-AcOEt 3:1). Yield 84%. .sup.1H NMR (400 MHz CDCl.sub.3-d): 8.28-8.251 (m, 2H), 7.91-7.88 (m, 2H), 7.27-7.25-(d, J=6.4 Hz, 2H), 7.18-7.12 (m, 2H), 2.02 (s, 3H) ppm. .sup.13C NMR (100 MHz CDCl.sub.3-d): 150.17, 145.28, 133.35, 131.20, 128.45, 127.27, 125.19, 124.30, 17.61 ppm. MS: m/z 314.8 [M+Na]+

(202) General procedure for the preparation of sulfonamides 60a-e and 61 a-d

(203) The opportune sulfonamide (400 mg, 1.35 mmol) was solubilized in 20 mL of anhydrous EtOH, and Palladium on charcoal (60 mg) was added. The reaction mixture was stirred under Hydrogen atmosphere for 1 h. Then the mixture was filtered-off on a celite pad, was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel with the appropriate eluent.

(204) 3-amino-N-(2-hydroxyphenyl)benzenesulfonamide (60a) (Purification eluent: Hexane-AcOEt 3:1). Yield 92%. .sup.1H NMR (Acetone): 8.29 (s, 1H), 7.27-7.24 (d, J=12 Hz, 1H), 7.14-7.09 (m, 2H), 6.99-6.97 (d, J=8 Hz, 1H), 6.95-6.92 (t, J=8 Hz, 1H), 6.82-6.75 (m, 2H), 6.74-6-72 (t, J=4 Hz, 1H), MS (ESI): m/z 286.8 [M+Na].sup.+.

(205) 4-amino-N-(2-hydroxyphenyl)benzenesulfonamide (61a) .sup.1H NMR (MeOD-d.sub.4): 7.55-7.53 (dd, J=8.8 Hz, 2H), 7.42-7.40 (dd, J=8.8 Hz, 2H), 7.22-7.18 (m, 1H), 6.90-6.84 (m, 2H), 6.70-6.66 (m, 2H), 6.55-6.53 (d, J=8.8 Hz, 1H) ppm. MS: m/z 286.8 [M+H]+.

(206) 3-amino-N-(4-methoxyphenyl)benzenesulfonamide (60b) (Purification eluent: Hexane-AcOEt 3:1). Yield 92%. .sup.1H NMR (Acetone): 7.3 (s, 1H), 7.26 (s, 1H), 7.17-7.14 (m, 2H), 6.96-6.94 (dd, J=8 Hz, 2H), 6.72-6.70 (dd, J=8.0 Hz, 2H), 3.72 (s, 3H) ppm. MS: m/z 300.8 [M+Na].sup.+.

(207) 3-amino-N-(2-(trifluoromethyl)phenyl)benzenesulfonamide (60c) (Purification eluent: Hexane-AcOEt 3:1). Yield 84%. .sup.1H NMR (Acetone): 7.63-7.61 (d, J=8 Hz, 1H), 7.51-7.58 (m, 2H), 7.24-7.20 (t, J=8 Hz, 1H), 7.19-7.17 (m, 2H), 7.07-7.05 (d, J=8 Hz, 1H), 6.90-6.88 (d, J=8 Hz, 1H), 5.10 (s, 1H). MS (ESI): m/z 338.8 [M+Na].sup.+.

(208) 4-amino-N-(2-(trifluoromethyl)phenyl)benzenesulfonamide (61c) (Purification eluent: Hexane-AcOEt 3:1). Yield 84%. .sup.1H NMR (Acetone): 7.53-7.51 (d, J=8 Hz, 1H), 7.49-7.46 (m, 2H), 7.45-7.43 (d, J=8 Hz, 2H), 7.30-7.28 (t, J=8 Hz, 1H), 6.62-6.60 (d, J=7.4 Hz, 1H), 5.10 (s, 1H). MS (ESI): m/z 338.8 [M+Na].sup.+.

(209) 3-amino-N-(o-tolyl)benzenesulfonamide (60d) .sup.1H NMR (Acetone): 8.14 (s, 1H), 7.2-6.92 (m, 6H), 6.92-6.86 (d, J=8 Hz, 1H), 6.85-6.84 (d, J=8 Hz, 1H), 2.11 (s, 3H) ppm. MS (ESI): m/z 262.9 [M+H].sup.+, 284.8 [M+Na].sup.+.

(210) 3-amino-N-(isoquinolin-6-yl)benzenesulfonamide (60e): Compound 59e (400 mg, 1.35 mmol) was solubilized in 20 mL of anhydrous EtOH, and Palladium on charcoal (60 mg) was added. The reaction mixture was stirred under Hydrogen atmosphere for 1 h. Then the mixture was filtered-off on a celite pad, concentrated in vacuo and the crude product was purified by flash chromatography on silica gel (PE-AcOEt: 4-1) Yield 67%. .sup.1H NMR (DMSO d-.sub.6): 10.23 (s, 1H), 9.25 (s, 1H), 9.41-9.40 (d, J=6.4 Hz, 1H), 7.95-7.84 (m, 2H), 7.59-7.56 (t, J=8 Hz, 1H), 7.43-7.41 (d, J=8.0 Hz, 1H), 7.09-7.06 (t, J=8.0 Hz, 1H), 6.80-6.78 (d, J=8.0 Hz, 1H), 6.66-6.64 (d, J=8.0 Hz), 5.50 (s, 2H) ppm. MS (ESI): m/z 299.8 [M+H].sup.+, 321.8 [M+Na].sup.+.

(211) General Procedure for the Preparation of Azides 62a-c and 63 a-d

(212) Amine (100 mg, 0.41 mmol) was dissolved in CH.sub.3CN and cooled to 0 C. in an ice-salt bath. To this stirred solution, was added tBuONO, and the mixture was stirred for 10 min, after this time, TMSN.sub.3 was added dropwise, during 10 minutes, and the resulting brown solution was stirred at r.t. One hour later the solvent was removed at reduced pressure and the residue was purified by flash chromatography on silica gel with the appropriate eluent.

(213) 3-azido-N-(2-hydroxyphenyl)benzenesulfonamide (62a). (Purification eluent: Hexane-AcOEt 3:1). .sup.1H NMR (Acetone): 8.42 (s, 1H), 7.58-7.56 (d, J=8 Hz, 1H), 7.53-7.49 (t, J=8.0 Hz, 1H), 7.44 (s, J=8 Hz, 1H), 7.34-7.32 (d, J=8.0 Hz, 1H), 7.28-7.27 (d, J=4.0 Hz, 1H), 7.00-6.96 (t, J=8.0 Hz, 1H) 6.81-6.77 (m, 2H). MS (ESI): m/z 288.8 [MH].sup..

(214) 4-azido-N-(2-hydroxyphenyl)benzenesulfonamide (63a). (Purification eluent: Hexane-AcOEt 3:1). .sup.1H NMR (MeOD-d.sub.4): 7.73-7.72 (dd, J=2.4 Hz, 2H), 7.36-7.35 (d, J=6.4 Hz, 1H), 7.09-7.07 (dd, J=8.8 Hz, 2H), 6.94-6.90 (m, H), 6.73-6.66 (m, 2H) ppm. MS: m/z 312.8 [M+Na].sup.+

(215) 3-azido-N-(2-methoxyphenyl) benzenesulfonamide (62b). (Purification eluent: Hexane-AcOEt 3:1). Yield 92%. .sup.1H NMR (Acetone): 7.5 (s, 1H), 7.26 (s, 1H), 7.27-7.24 (m, 2H), 7.06-7.04 (dd, J=8 Hz, 2H), 6.74-6.72 (dd, J=8.0 Hz, 2H), 3.73 (s, 3H) ppm. MS: m/z 300.8 [M+Na].sup.+.

(216) 3-azido-N-(o-tolyl)benzenesulfonamide (62c). (Purification eluent: Hexane-AcOEt .sup.1H NMR (400 MHz CDCl.sub.3-d): 7.51-7.49 (d, J=8 Hz, 1H), 7.43-7.39 (t, J=8 Hz, 1H), 7.36 (s, 1H), 7.30-7.28 (d, J=8 Hz, 1H), 7.15-7.09 (m, 4H), 6.75 (s, 1H), 2.02 (s, 3H) ppm. MS (ESI): m/z 310.8 [M+Na].sup.+.

(217) 3-azido-N-(2-(trifluoromethyl)phenyl)benzenesulfonamide (62d). (Purification eluent: Hexane-AcOEt 4:1). .sup.1H NMR (400 MHz CDCl.sub.3-d): 7.84-7.81 (d, J=8.4 Hz, 1H), 7.56-7.50 (m, 3H), 7.43-7.37 (m, 2H), 7.27-7.23 (t, J=7.6 Hz, 1H), 7.18-7.16 (d, J=8 Hz, 1H), 6.87 (s, 1H) ppm. MS (ESI): m/z 364.8 [M+Na].sup.+.

(218) 4-azido-N-(2-(trifluoromethyl)phenyl)benzenesulfonamide (63c). (Purification eluent: Hexane-AcOEt 4:1). .sup.1H NMR (400 MHz CDCl.sub.3-d): 7.81-7.79 (d, J=7.6 Hz, 1H), 7.74-7.71 (d, J=7.4 Hz, 1H), 7.52-7.46 (m, 2H), 7.22-7.18 (t, J=8 Hz, 1H), 7.02-6.98 (m, 3H) ppm. m/z 364.7 [M+Na].sup.+.

(219) 3-azido-N-(isoquinolin-6-yl)benzenesulfonamide (62e): The opportune amine (100 mg, 0.41 mmol) was dissolved in CH.sub.3CN and cooled to 0 C. in an ice-salt bath. To this stirred solution, was added tBuONO, and the mixture was stirred for 10 min, after this time, TMSN.sub.3 was added dropwise, during 10 minutes, and the resulting brown solution was stirred at r.t. One hour later the solvent was removed at reduced pressure and the residue was purified by flash chromatography on silica gel (PE-AcOEt: 4-1) Yield 67%. .sup.1H NMR (DMSO d-.sub.6): .sup.1H NMR (DMSO d-.sub.6): 9.03 (s, 1H), 8.62 (s, 1H), 8.26 (s, 1H), 7.74-7.33 (m, 6H), 7.09-7.07 (d, J=8.0 Hz, 1H) ppm. MS (ESI): m/z 325.8 [M+H].sup.+, 347.7 [M+Na].sup.+.

(220) General Procedure for the Preparation of Compounds 64a, 64b, 64c, 64d, 64e, 64f 65a, 65c, 66d, 67d and 68.

(221) The appropriate alkyne (6.08 mmol) and the opportune azide (5.07 mmol) were suspended in a 1:1 mixture of water and t-BuOH (1.5 mL each) in a 10 mL glass vial equipped with a small magnetic stirring bar. To this, was added sodium ascorbate (2.5 mmol) and copper(II) sulfate pentahydrate (2.50 mmol). The mixture was then heated for 10 min. at 125 C. under microwave irradiation, using an irradiation power of 300 W. After that time the solvent was removed at reduced pressure water was added and the mixture was extracted with EtOAc (320 mL). The organic layers were collected, washed with Brine and dried over Na.sub.2SO.sub.4. The crude was purified by flash chromatography on silica gel using the opportune eluent to give the desired triazole compounds 64a, 64b, 64c, 64d, 64e, 64f, 65a, 65c, 66d, 67d and 68.

(222) 3-(4-butyl-1H-1,2,3-triazol-1-yl)-N-(2-hydroxyphenyl)benzenesulfonamide (64a). (Purification eluent: Hexane-AcOEt 3:1). Yield 82%. .sup.1H NMR (400 MHz, Acetone): 8.48 (s, 1H), 8.34-8.31 (m, 2H), 8.11-8.09 (d, J=8 Hz, 1H), 7.81-7.79 (d, J=8 Hz, 1H), 7.71-7.67 (t, J=8 Hz, 1H), 7.37-7.35 (d, J=8 Hz, 1H), 6.99-6.95, (t, J=8 Hz, 1H), 6.81-6.77 (m, 2H). .sup.13C NMR (100 MHz, Acetone): 149.88, 142.46, 137.68, 130.44, 137.68, 130.44, 126.66, 126.50, 124.40, 124.19, 123.58, 119.90, 119.47, 118.32, 115.59, 31.30, 24.94, 21.95, 13.19. MS (ESI): m/z 370.7 [MH].sup..

(223) 4-(4-butyl-1H-1,2,3-triazol-1-yl)-N-(2-hydroxyphenyl)benzenesulfonamide (65a). (Purification eluent: Hexane-AcOEt 4:1). Yield 80 .sup.1H NMR (400 MHz, MeOD-d.sub.4): 8.34 (s, H), 7.93-7.87 (m, 4H), 7.33-7.31 (d, J=6.8 Hz, 1H), 6.96-6.92 (m, 1H), 6.765-7.727 (t, J=7.6 Hz, 1H), 6.67-6.65 (d, J=8 Hz, 1H), 2.78-2.74 (t, J=7.6 Hz, 2H) 1.74-1.66 (quint, 2H), 1.45-1.36 (sx, 2H), 1.27-1.22 (t, J=7.2 Hz, 3H) ppm. .sup.13C NMR (100 MHz, MeOD-d.sub.4): 150.64, 149.22, 140.03, 129.07, 126.59, 125.18, 124.12, 119.86, 115.45, 31.12, 24.93, 22.10, 12.91 ppm. MS: m/z 372.8 [M+H]+, 394.8 [M+Na].sup.1

(224) 3-(4-butyl-1H-1,2,3-triazol-1-yl)-N-(4-methoxyphenyl)benzenesulfonamide (64b). (Purification Eluent: Hexane-AcOEt 3:1). Yield 79%. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.10 (s, 1H), 7.95-7.93 (d, J=7.6 Hz, 1H), 7.71 (s, 1H), 7.68-7.66 (d, J=7.7 Hz, 1H), 7.61 (s, 1H), 7.56-7.52 (t, J=7.9 Hz, 1H), 7.07-7.04 (dd, J=8.2 Hz, 2H), 6.77-6.75 (dd, J=8.2 Hz, 2H), 3.73 (s, 3H), 2.78-2.75 (t, J=7.7 Hz, 2H), 1.71-1.64 (quin. J=7.4 Hz, 2H), 1.43-1.36 (sx, J=7.6 Hz, 2H), 0.95-0.91 (t J=7.6 Hz, 3H) ppm. .sup.13C NMR (100 MHz, MeOD-d.sub.4): 158.45, 149.70, 141.20, 137.55, 130.75, 127.59, 125.89, 124.43, 119.27, 118.84, 114.46, 55.90, 31.84, 25.52, 21.87, 13.85 ppm. MS: m/z 372.8 [M+H]+, 394.8 [M+Na].sup.1

(225) 3-(4-butyl-1H-1,2,3-triazol-1-yl)-N-(o-tolyl)benzenesulfonamide (64c). (Purification eluent: Hexane-AcOEt 3:1). Yield 90%. .sup.1H NMR (400 MHz, Acetone): 8.56 (s, 1H), 8.35.8.33 (d, J=8 Hz, 1H), 8.25-8.23 (d, J=8.0 Hz, 1H), 8.14-8.11 (t, J=7.2 Hz, 1H), 7.74-7.72 (m, 2H), 7.17-7.10 (m 4H), 2.77-2.73 (t, J=7.4 Hz, 2H), 1.73-1.65 (q, J=8.0 Hz, 2H), 1.43-1.37 (quint, J=8.0 Hz, 2H), 0.95-0.91 (t, J=8 Hz, 1H) ppm. .sup.13C NMR (100 MHz, Acetone): 149.06, 142.56, 137.76, 134.78, 134.16, 130.91, 130.72, 126.78, 126.51, 126.37, 126.28, 123.51, 119.46, 118.11 31.22, 24.95, 21.95, 17.18, 13.18 ppm. MS (ESI): m/z 371.7 [M+H].sup.+.

(226) 3-(4-butyl-1H-1,2,3-triazol-1-yl)-N-(2-(trifluoromethyl)phenyl)benzenesulfonamide (64d) (Purification eluent: Hexane-AcOEt 3:1). Yield 90%. .sup.1H NMR (Acetone): 8.78 (s, 1H), 8.41-8.37 (m, 3H), 8.18-8.16 (d, J=8.2 Hz, 1H), 7.89-7.87 (d, J=7.6 Hz, 1H), 7.82-7.78 (t, J=7.8 Hz, 1H), 7.69-7.61 (m 2H), 7.54-7-52 (d, J=8 Hz, 1H), 7.45-7.44 (t, J=7.4 Hz, 1H), 2.77-2.73 (t, J=7.4 Hz, 2H), 1.71-1.67 (q, J=8.0 Hz, 2H), 1.45-1.35 (quint, J=8.0 Hz, 2H), 0.94-0.89 (t, J=8.0 Hz, 1H) ppm. .sup.13C NMR (Acetone): 149.1, 142.66, 137.89, 134.15, 133.28, 130.93, 127.40, 126.90, 126.28, 124.80, 123.85, 122.29, 119.54, 118.03, 31.22, 24.95, 21.95, 13.18 ppm. MS (ESI): m/z 425 [M+H].sup.+.

(227) 4-(4-butyl-1H-1,2,3-triazol-1-yl)-N-(2-(trifluoromethyl)phenyl)benzenesulfonamide (65c). (Purification eluent: Hexane-AcOEt 3:1). Yield 93%. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.79-7.81 (m, 4H) 7.75 (s, 1H), 7.57-7.53 (t, J=8 Hz, 1H), 7.51-7.49 (d, J=8 Hz, 1H), 8.41-8.37 (m, 3H), 8.18-8.16 (d, J=8.2 Hz, 1H), 7.89-7.87 (d, J=7.6 Hz, 1H), 7.82-7.78 (t, J=7.8 Hz, 1H), 7.69-7.61 (m 2H), 7.54-7-52 (d, J=8 Hz, 1H), 6.94, (s, 1H), 2.79-2.75 (t, J=7.4 Hz, 2H), 1.73-1.65 (quint, J=8.0 Hz, 2H), 1.43-1.36 (sx, J=8.0 Hz, 2H), 0.95-0.91 (t, J=8.0 Hz, 1H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3-d): 149.9, 140.8, 137.99, 133.88, 133.56, 129.53, 126.71, 125.70, 124.94, 124.09, 122.27, 120.88, 118.45, 31.32, 25.24, 22.24, 13.76 ppm. MS (ESI): m/z 425 [M+H].sup.+.

(228) 3-(4-butyl-1H-1,2,3-triazol-1-yl)-N-(isoquinolin-6-yl)benzenesulfonamide (64e). (Purification eluent: Hexane-AcOEt 3:1). Yield 77%. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 9.23 (s, 1H), 8.42 (s, 1H), 8.26 (s, 1H), 7.89-7.83 (m, 3H), 7.66-7.62 (m, 3H), 7.55-7.46 (m, 2H), 2.74-2.71 (t, J=7.8 Hz, 2H), 1.66-1.59 (quint, J=8.0 Hz, 2H), 1.39-1.25 (sx, J=8.0 Hz, 2H), 0.90-0.86 (t, J=8.0 Hz, 1H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3-d): 152.43, 149.84, 142.93, 141.34, 137.68, 132.70, 131.10, 130.51, 129.38, 128.51, 127.38, 126.85, 124.13, 118.81, 115.75, 31.36, 25.25, 22.26, 13.62 ppm. MS (ESI): m/z 408.8 [M+H].sup.+.

(229) 3-(4-(ethoxymethyl)-1H-1,2,3-triazol-1-yl)-N-(2-(trifluoromethyl)phenyl) benzenesulfonamide (66d): (Purification eluent: PE/EtOAc 7:2) Yield 85% white solid .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.09 (1H, s), 7.99-7.97 (d, J=6.8 Hz, 1H), 7.79-7.75 (t, 8.8 Hz, 1H), 7.60-7.47 (m, 3H), 7.26-7.22 (t, J 7.2 Hz, 1H), 4.66 (s, 2H), 3.63-3.58 (q, 2H), 1.24-1.20 (t, J=6.8 Hz, 3H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3-d): 146.95, 140.78, 137.44, 133.39, 130.80, 126.99, 126.07, 125.84, 124.87, 124.69, 122.09, 120.58, 118.71, 66.39, 63.99, 15.07 ppm. MS (ESI): m/z 427 [M+H].sup.+.

(230) 3-(4-isopentyl-1H-1,2,3-triazol-1-yl)-N-(2 (trifluoromethyl)phenyl) benzene sulfonamide (67d): (Purification eluent: PE/EtOAc 7:2), Yield 78%, yellow solid. .sup.1H NMR (CDCl.sub.3): 8.06 (s, 1H), 8.01-8.00 (d, J 7.6 Hz, 1H), 7.84-7.82 (d, J=8.0 Hz, 1H), 7.76-7.74 (d, J=7.6 Hz, 1H), 7.69 (1H, s), 7.60-7.56 (t, J=8.4 Hz, 1H), 7.53-7.49 (t, J 7.6 Hz, 2H), 7.27-7.25 (d, J=8.0 Hz, 1H), 2.80-2.78 (m, 2H), 1.62 (m, 3H), 0.99-0.94 (m, 6H) ppm. .sup.13C NMR (CDCl.sub.3): 149.95, 145.96, 143.95, 137.71, 133.39, 160.71, 126.68, 125.29, 124.91, 124.15, 118.51, 38.27, 27.62, 23.51, 22.36 ppm. MS: m/z 438.8 [M+H].sup.+

(231) 3-(4-(ethoxymethyl)-1H-1,2,3-triazol-1-yl)-N-(isoquinolin-6-yl)benzenesulfonamide (68e): (Purification eluent: Hexane-AcOEt 3:1). Yield 74%. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.22 (s, 1H), 7.93 (s, 1H), 7.90-7.17 (m, 3H), 7.70-7.67 (d, J 8.0 Hz, 1H), 7.63.7.61 (d, J=8.0 Hz, 1H), 7.56-7.48 (m, 2H), 4.66 (s, 2H), 3.62-3.57 (q, J 7.4 Hz, 2H), 1.22-1.18 (t, J=7.8 Hz, 3H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3-d): 152.57, 146.93, 143.22, 141.49, 137.46, 132.52, 130.90, 128.22, 127.44, 124.33, 120.66, 119.97, 66.51, 63.97, 15.11 ppm. MS (ESI): m/z 425 [M+H].sup.+.

Example 11

(232) ##STR00122##

(233) 3-cyano-N-(2-(trifluoromethyl)phenyl)benzenesulfonamide (69) To a stirred solution of 68 (1 eq.) in 5 mL of anhydrous pyridine, was added sulphonyl chloride 57 d (1.1 eq) at 0 C. The corresponding solution was stirred at r.t. under nitrogen atmosphere, for 5 h. After completion of the reaction the mixture was acidified with 1N HCl, the aqueous phase was extracted with several times and the combined organic phases were dried (Na.sub.2SO.sub.4) and concentrated. (PE-AcOEt 7:3). Yield 75%, white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 7.99-7.94 (m, 2H), 7.82-7.80 (m, 2H), 7.60-7.51 (m, 3H), 7.30-7.26 (t, J=8 Hz, 1H), 6.97 (s, 1H) ppm. MS (ESI): m/z 425 [M+H].sup.+.

(234) 3-(2H-tetrazol-5-yl)-N-(2-(trifluoromethyl)phenyl)benzenesulfonamide (70) A mixture of 69 (500 mg, 1.53 mmol), NaN.sub.3 (299 mg, 4.60 mmol), NH.sub.4Cl (328 mg, 6.12 mmol) in DMF (5 mL), was heated at 130 C. for 6 h. After that time the rxn was allowed to r.t. water was added with continuous stirring. The mixture was then acidified to pH 2. The mixture was extracted with DCM (325 mL) and washed with aq 5% solution of LiCl, then dried over anhydrous Na.sub.2SO.sub.4. The solvent was removed at reduced pressure and the residue purified by flash chromatography on silica gel (DCM-MeOH 94:6). Yield 95%, white solid. mp 138.40 C. .sup.1HNMR (400 MHz, CDCl.sub.3-d): 8.47 (s, 1H), 8.20-8.18 (d, J=7.6 Hz, 1H), 7.88 (s, 1H), 7.75-7.73 (d, J=8.0 Hz, 1H), 7.48-7.40 (m, 2H), 7.31-7.28 (m, 2H), 7.07-7.03 (t, J=7.6 Hz, 1H) ppm. .sup.13CNMR (100 MHz, CDCl.sub.3-d): 163.42, 140.86, 133.70, 133.01, 131.54, 130.13, 130.00, 129.15, 127.37, 126.62, 126.10, 125.85, 124.65, 123.08, 119.22 ppm MS

(235) 3-(2H-tetrazol-5-yl)-N-(2-(trifluoromethyl)phenyl)benzenesulfonamide benzenesulfonamide potassium salt (71). 70 (50 mg, 0.13 mmol) and K.sub.2CO.sub.3 (37.42 mg, 0.26 mmol) were dissolved in 1.5 mL of water. After the evolution of CO.sub.2 ceased, the solution was refluxed for 15 minutes and afterwards evaporated to dryness. The resulting solid was recrystallized from ACN. Mp 224-226 Yield 82% white solid .sup.1HNMR (400 MHz, CDCl.sub.3-d): 8.02 (s, 1H), 7.81-7.79 (d, J=7.6 Hz, 1H), 7.56-7.54 (d, J=8.0 Hz, 1H), 7.44-7.40 (t, J=7.6 Hz, 1H), 6.44-6.40 (t, J=7.9 Hz, 1H) ppm.

Example 12

(236) ##STR00123##

(237) General Procedure for the Preparation of Compounds 74 and 75.

(238) Opportune 4-nitroaniline (7.24 mmol) was dissolved in CH.sub.3CN and cooled to 0 C. in an ice-salt bath. To this stirred solution, was added tBuONO (8.69 mmol), and the mixture was stirred for 10 min, after this time, TMSN.sub.3 (10.86 mmol) was added dropwise, during 10 minutes, and the resulting brown solution was stirred at r.t. One hour later the solvent was removed at reduced pressure and the residue was purified by flash chromatography on silica gel

(239) 1-azido-2-methoxy-4-nitrobenzene (74): (Purification eluent: PE/AcOEt 7:3). Yield 88%, white solid. .sup.1HNMR (400 MHz, CDCl.sub.3-d): 7.74-7.72 (d, J=8.0 Hz, 2H), 7.65 (s, 1H), 6.96-6.94 (d, J=8.0 Hz, 2H), 3.91 (s, 3H) ppm. .sup.13CNMR (100 MHz, CDCl.sub.3-d): 152.03, 144.93, 153.31, 120.03, 117.03, 106.97, 56.42 ppm. MS (ESI) m/z 195.1 [M+H].sup.+, 218.1 [M+Cl].sup..

(240) 1-azido-2-fluoro-4-nitrobenzene (75): (Purification eluent: PE/EA 9:1). Yield 60%, yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.02-7.92 (m, 2H), 7.19-7.15 (t, J=16 Hz, 1H) ppm.

(241) General Procedure for the Preparation of Compounds 76 and 77.

(242) The appropriate alkyne 14a or 14b (0.10 mmol) and the opportune azide (0.09 mmol) were suspended in a 1:1 mixture of water and t-BuOH (1.5 mL each) in a 10 mL glass vial equipped with a small magnetic stirring bar. To this, was added sodium ascorbate (0.1 equiv) and copper(II) sulfate pentahydrate (0.10 mmol). The mixture was then heated for 10 min. at 125 C. under microwave irradiation, using an irradiation power of 300 W. After this time the precipitate was filtered-off and purified on silica, to give final products 76 or 77.

(243) 4-isopentyl-1-(2-methoxy-4-nitrophenyl)-1H-1,2,3-triazole (76): (Purification eluent: PE/EA 8:3). Yield 94%, white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.24 (s, 1H), 8.00-7.98 (d, J=8.0 Hz, 1H), 7.84-7.80 (m, 2H), 2.76-2.72 (t, J=7.2 Hz, 2H), 1.60-1.54 (m, 3H), 0.88-0.87 (d, J=6.0 Hz) ppm. MS (ESI) m/z 291.32 [MH].sup.+

(244) 4-butyl-1-(2-fluoro-4-nitrophenyl)-1H-1,2,3-triazole (77). (Purification eluent: PE/EA 7:3). Yield 63%, yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.24-8.20 (t, J=8.0 Hz, 1H), 8.12-8.10 (m, 2H), 7.91-7.90 (d, J=4.0 Hz, 1H), 2.72-2.69 (t, J=12.0 Hz, 2H), 1.65-1.58 (m, 2H), 1.36-1.27 (m, 2H), 0.86-0.82 (m, 3H) ppm.

(245) General Procedure for the Preparation of Compounds 78 and 79

(246) The opportune triazole compound 76, or 78 (1.60 mmol) was solubilized in 30 mL of MeOH, and 10% Palladium on charcoal (25 mg) was added. The reaction mixture was stirred under Hydrogen atmosphere for 1 h, then the mixture was filtered off on a celite pad, the solvent evaporated at reduced pressure to obtain 78 or 79 as pure compounds.

(247) 4-(4-isopentyl-1H-1,2,3-triazol-1-yl)-3-methoxyaniline (78): The product was obtained as a pure compound. Yield 99%, yellow solid. Yield .sup.1H NMR (400 MHz, CDCl.sub.3-d): 7.58 (s, 1H), 7.27-7.25 (dd, J=8.0 Hz, 2H), 6.28 (s, 1H), 6.22-6.20 (dd, J=8.0 Hz, 2H), 4.14 (s, 2H), 3.64 (s, 3H), 2.73-2.69 (t, J=7.6 Hz, 2H), 1.57-1.54 (m, 3H), 0.89-0.88 (d, J=5.6 Hz, 6H) ppm.

(248) 4-(4-butyl-1H-1,2,3-triazol-1-yl)-3-fluoroaniline (79). The product was obtained as a pure compound. Yield 99%, white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 7.57 (s, 1H), 7.41-7.39 (d, J=8.0 Hz 1H), 6.44-6.42 (d, J=8.0 Hz, 2H), 4.25 (s, 2H), 1.65-1.62 (d, J=6.0 Hz, 2H), 1.65-1.62 (m, 2H), 1.35-1.32 (m, 2H), 0.89-0.85 (m, 3H) ppm. MS (ESI) m/z 235 [M+H].sup.+.

(249) General Procedure for the Preparation of Compounds 80 and 81.

(250) The opportune aniline 78 or 79 (0.10 mmol) was added to a solution of 2-(Trifluoromethyl)phenyl isocyanate (0.15 mmol) in anhydrous DCM (15 mL) in one portion. The solution was stirred for 9 hours at r.t. under a nitrogen atmosphere. The solvent was removed at reduced pressure and the residue purified on silica to afford the final product 80 or 81.

(251) 1-(4-(4-isopentyl-1H-1,2,3-triazol-1-yl)-3-methoxyphenyl)-3-(2-(trifluoromethyl) phenyl)urea (80): (Purification eluent: DCM/MeOH 98:2). Yield 78%, white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.12-8.06 (m, 2H), 7.92 (s, 1H), 7.61-7.54 (m, 3H), 7.26-7.21 (m, 2H), 7.18 (s, 1H), 3.97 (s, 3H), 2.83-2.80 (t, J=7.8 Hz, 2H), 1.71-1.63 (m, 3H), 0.98-0.97 (d, J=7.8 Hz, 6H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3): 153.05, 152.05, 148.40, 136.61, 134.63, 132.90, 127.92, 126.70, 126.17, 124.85, 124.78, 122.62, 122.53, 121.46, 121.08, 114.12, 56.43, 38.52, 27.77, 23.66, 22.52 ppm. MS (ESI) m/z 448.3 [MH].sup.+

(252) 1-(4-(4-butyl-1H-1,2,3-triazol-1-yl)-3-fluorophenyl)-3-(2-(trifluoromethyl)phenyl)urea (81). (Purification eluent: DCM/MeOH 98:2). Yield 70%, yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 7.99-7.97 (d, J=12.0 Hz, 1H), 7.91-7.89 (d, J=8.0, 1H), 7.86-7.79 (m, 2H), 7.75 (s, 1H), 7.72-7.68 (t, J=8.0, 1H), 7.60-7.53 (m, 2H), 7.27-7.20 (m, 2H), 2.79-2.75 (t, J=8.0 Hz, 2H), 1.71-1.67 (t, 16.0 Hz, 2H), 1.42-1.37 (m, 2H), 0.94-0.90 (t, 16.0 Hz, 3H) ppm. MS (ESI) m/z 420 [MH].sup..

Example 13

(253) ##STR00124##

(254) 2-(4-isopentyl-1H-1,2,3-triazol-1-yl)-5-nitro pyri dine (84). A solution of 2-chloro-5-nitropyridine 82 (100 mg, 0.63 mmol) in a mixture of ethanol (8 mL) and water (3 mL) was carefully treated with NaN.sub.3 (81 mg, 1.26 mmol). Concentrated HCl (0.8 mL) was added dropwise at rt. The reaction was stirred at reflux on, then cooled to rt. After that time saturated NaHCO.sub.3 was added and the pH adjusted to 7. DCM (15 mL) was added and the rxn was washed with water. The organic layers were dried over Na.sub.2SO.sub.4 and concentrated to afford a yellow residue. The residue and the appropriate alkyne (90 L, 0.75 mmol) were suspended in a 1:1 mixture of water and THF (1.5 mL each). To this, was added sodium ascorbate (1.0 equiv) and copper(II) sulfate pentahydrate (1.0 mmol). The mixture was stirred at r.t. for 5 h. After that time the reaction was partitioned between sat. aq. solution of NH.sub.4Cl and AcOEt, and stirred for 15 min. The organic layer was separated, dried over Na.sub.2SO.sub.4 and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel (DCM/MeOH 98:2). Yield 75%, yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 9.28 (s, 1H), 8.67-8.64 (m, 1H), 8.36-8.32 (m, 2H), 2.80-2.76 (t, J=7.8 Hz, 2H), 1.67-1.58 (m, 3H), 0.84-0.82 (d, J=8.0 Hz, 6H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3-d): 152.24, 150.03, 144.99, 143.23, 134.59, 118.55, 114.44, 113.60, 38.08, 27.56, 23.48, 22.32 ppm. MS (ESI) m/z 260.3 [MH].sup.

(255) 6-(4-isopentyl-1H-1,2,3-triazol-1-yl)pyridin-3-amine (85): 84 (1.60 mmol) was solubilized in 30 mL of anhydrous MeOH, and 10% Palladium on charcoal (25 mg) was added. The reaction mixture was stirred under Hydrogen atmosphere for 1 h, then the mixture was filtered off on a celite pad, the solvent evaporated at reduced pressure. The product was obtained as a pure compound. Yield 99%, yellow solid. Yield .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.14 (s, 1H), 7.92-7.90 (m, 2H), 7.17-7.14 (m, 1H), 3.89 (s, 2H), 2.80-2.76 (t, J=7.8 Hz, 2H), 1.74-1.58 (m, 3H), 0.95-0.93 (d, J=8.0 Hz, 6H) ppm. MS (ESI) m/z 232.3 [M+H].sup.+.

(256) 1-(6-(4-isopentyl-1H-1,2,3-triazol-1-yl)pyridin-3-yl)-3-(2-(trifluoromethyl)phenyl)urea (86). Aniline 85 (0.10 mmol) was added to a solution of 2-(Trifluoromethyl)phenyl isocyanate (0.15 mmol) in anhydrous CH.sub.2Cl.sub.2 (15 mL) in one portion. The solution was stirred for 9 hours at r.t. under a nitrogen atmosphere. The solvent was removed at reduced pressure and the residue purified on silica to furnish the final product as white solid. (Purification eluent: DCM-MeOH 98:2). Yield 61%, white solid. .sup.1H NMR (400 MHz, Acetone-d.sub.6): 9.14 (s, 1H), 8.66 (s, 1H), 8.37 (s, 1H), 8.28-8.24 (d, J=8.0 Hz, 1H), 8.14-8.12 (d, J=8.0 Hz, 1H), 8.06-8.04 (d, J=8.0 Hz, 1H), 7.81 (s, 1H), 7.70-7.64 (m, 2H), 7.33-7.30 (t, J=8.0 Hz, 1H), 2.80-2.75 (t, J=7.7 Hz, 2H), 1.64-1.61 (m, 3H), 0.96-0.94 (d, J=8.0 Hz, 6H) ppm. .sup.13C NMR (100 MHz, Acetone-d.sub.6): 152.31, 148.41, 144.17, 138.61, 138.26, 136.46, 132.84, 128.80, 125.95, 125.65, 123.96, 117.98, 117.71, 113.35, 38.34, 27.33, 23.23, 21.91, 21.64 ppm. MS (ESI) m/z 419.3 [M+H].sup.+.

Example 14

(257) ##STR00125##

(258) 4-acetylisochroman-1,3-dione (88): Pyridine (2 mL) was slowly added to a slurry of homophtalic acid (1000 mg, 5.55 mmol) in acetic anhydride at 0 C. with stirring. The resulting solution was stirred at room temperature for 5 h. After that time Et.sub.2O was added and the resulting white solide was collected by filtration and rinsed twice with ether. Yield 75% white solid. .sup.1H NMR (400 MHz, CDCl.sub.3 d): 8.25-8.23 (d, J=8.0 Hz, 1H), 7.70-7.68 (d, J=8.0 Hz, 1H), 7.60-7.58 (d, J=8.0 Hz, 1H), 7.39-7.37 (d, J=8.0 Hz, 1H), 2.64 (s, 3H), 2.62 (s, 1H),

(259) 3-methylisoquinolin-1-ol (89): To 4-acetyl isochroman-1,3-dione (1000 mg, 4.90 mmol) was added slowly sat aq. NH.sub.4OH (9 mL). The resulting bright yellow suspension was heated in a sealed tube at 95 C. for 5 h. Then the reaction mixture was cooled to r.t and diluted with water. The resulting white solid was collected by filtration at reduced pressure and dried. Yield 99%. White solid. .sup.1H NMR (400 MHz, CDCl.sub.3 d): 11.61 (br s, 1H), 8.39-8.37 (d, J=8.0 Hz, 1H), 7.62-7.58 (t, J=8.0 Hz, 1H), 7.46-7.39 (m, 2H), 6.30 (s, 1H), 2.40 (s, 3H) ppm.

(260) 3-methyl-4-nitroisoquinolin-1-ol (90): To a solution of 89 (800 mg, 5.02 mmol), in acetic acid (7 mL), was slowly added 90% nitric acid (fuming) (2 mL), at 0 C. with stirring. The reaction mixture is allowed to warm to rt and stirred for 3 h. Water was added and the resulting solid was collected by filtration and dried. Yield 90% yellow solid .sup.1H NMR (400 MHz, CDCl.sub.3 d): 12.03 (br s, 1H), 8.21-8.19 (d, J=8.0 Hz, 1H), 7.82-7.78 (t, J 8.0 Hz, 1H), 7.73-7.17 (d, 1H), 7.58-7.54 (t, J=8.0 Hz, 1H), 2.42 (s, 3H) ppm.

(261) 1-chloro-3-methyl-4-nitroisoquinoline (91): A mixture of 90 (100 mg, 0.49 mmol), and POCl.sub.3 (5 mL) was heated with stirring at 110 C. for 1 h. POCl.sub.3 was removed by distillation, and the resulting residue was neutralized with aq NaHCO.sub.3 and extracted with AcOEt (325 mL). The organic layers were collected and washed with brine, dried over anhydrous Na.sub.2SO.sub.4 filtered and evaporated under reduced pressure to obtain pure compound. Yield 99% .sup.1H NMR (400 MHz, CDCl.sub.3 d): 8.31-8.29 (d, J=8.0 Hz, 1H), 7.84-7.80 (t, J=8.0 Hz, 1H), 7.71-7.68 (m, 1H), 2.65 (s, 3H) ppm.

(262) 1-chloro-3-methylisoquinolin-4-amine (53g). To a solution of 91 (800 mg, 3.59 mmol) in concentrated HCl (15 mL), was added SnCl.sub.2 2H.sub.2O. The reaction mixture was stirred for 18 h at rt. After that time was poured into ice-water and the pH adjusted to 8 by addition of 1N NaOH. The rxn mixture was extracted with AcOEt (325 mL) and the combined organic layers were dried over Na.sub.2SO.sub.4 to obtain a residue that was crystallized from Ethanol to obtain pure compound. Yield 84% .sup.1H NMR (400 MHz, CDCl.sub.3 d): 8.23-8.20 (d, J=8.0 Hz, 1H), 7.75-7.73 (d, J=8.0 Hz, 1H), 7.73-7.64 (t, 1H), 7.59-7.55 (t, J=8.0 Hz, 1H), 3.95 (s, 2H), 2.53 (s, 3H) ppm. MS (ESI) m/z 193.0 [M+H].sup.+.

Example 15

(263) ##STR00126##

(264) 4-methyl-3-nitrophenol (93): 92 (200 mg, 1.31 mmol) was dissolved in a 3:1 mixture of H.sub.2SO.sub.4H.sub.2O. The resulting mixture was heated to 100 C. for 30 minutes. After that time, rxn was cooled to 0 C. and a solution of NaNO.sub.2 was added dropwise. After 1 hr the mixture was heated to reflux. After completion of the reaction the mixture was extracted with EtOAc several times and the combined organic phases were dried (Na.sub.2SO.sub.4) and concentrated. The resulting mixture was purified by flash chromatography (Purification eluent: PE-AcOEt 9:1). Yellow solid, Yield 70%. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.48 (s, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.01 (dd, J=8.4, 2.4 Hz, 1H), 5.84 (s, 1H), 2.48 (s, 3H) ppm.

(265) General Procedure for the Synthesis of 94a and 94b:

(266) 93 (500 mg, 3.26 mmol) was dissolved in anhydrous DMF (3 mL) under nitrogen atmosphere. To this, NaH (86 mg, 3.58 mmol) was added at 0 C., in one portion. After 20 minutes, a solution of the opportune halogen derivative (3.9 mmol) in DMF (1 mL) (cyclopentyl iodide for 94a or chloromethyl methyl ether for 94b) was added via cannula. The resulting solution was stirred at rt for 2 hrs. After completion of the reaction a water was added, and the mixture was extracted with EtOAc several times, washed with 5% LiCl(aq), and the combined organic phases were dried (Na.sub.2SO.sub.4) and concentrated.

(267) 4-(cyclopentyloxy)-1-methyl-2-nitrobenzene (94a): (Purification eluent: PE-AcOEt 95:5). Yield 70%. yellow liquid, .sup.1H NMR (400 MHz, CDCl.sub.3) 7.44-7.43 (m, 1H), 7.16 (d, J=8.4 Hz, 1H), 6.98 (dd, J=8.4, 2.5 Hz, 1H), 4.81-4.68 (m, 1H), 2.48 (s, 3H), 1.98-1.69 (m, 6H), 1.67-1.52 (m, 2H) ppm. MS (ESI) m/z 222.0 [M+H].sup.+.

(268) 4-(methoxymethoxy)-1-methyl-2-nitrobenzene (94b): 94b was obtained as a pure compound. Yield 99%. yellow liquid, .sup.1H NMR (400 MHz, CDCl.sub.3) 7.62 (s, 1H), 7.34-6.90 (m, 2H), 5.16 (s, 2H), 3.45 (s, 3H), 2.49 (s, 3H). ppm. MS (ESI) m/z 198.2 [M+H].sup.+.

(269) General Procedure for the Synthesis of 54a and 54b:

(270) The opportune nitro compound 94a or 94b (0.40 mmol) was solubilized in 30 mL of MeOH, and 10% Palladium on charcoal (5 mg) was added. The reaction mixture was stirred under Hydrogen atmosphere for 1 h, then the mixture was filtered-off on a celite pad and the solvent was evaporated at reduced pressure to furnish 54a or 54b as a pure compound.

(271) 5-(cyclopentyloxy)-2-methylaniline (54a): yellow solid, Yield 99%. .sup.1H NMR (400 MHz, CDCl.sub.3) 6.92 (d, J=8.0 Hz, 1H), 6.31-6.24 (m, 2H), 4.93-4.49 (m, 1H), 3.57 (s, 2H), 2.10 (s, 3H), 1.86-1.78 (m, 6H), 1.61 (s, 2H) ppm. MS (ESI) m/z 192.3[M+H].sup.+.

(272) 5-(methoxymethoxy)-2-methylaniline (54b): yellow solid, Yield 99%. .sup.1H NMR (400 MHz, CDCl.sub.3-d) 6.93 (d, J=8.8 Hz, 1H), 6.40 (m, 2H), 5.11 (s, 2H), 3.59 (s, 2H), 3.47 (s, 3H), 2.09 (s, 3H). MS (ESI) m/z 168.1[M+H].sup.+.

Example 16

(273) ##STR00127##

(274) 4-(4-methyl-3-nitrophenyl)but-3-en-2-one (96): To a mixture of 3-nitro-4-methylbenzaldehyde (300 mg, 1.8 mmol), acetone (20 mL) and water (10 mL) 5% aqueous NaOH (1 mL) was slowly added at 40 C. After 20 minutes, acetone was removed under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure. (yield 76%) yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.93 (s, 1H), 7.51 (s, 1H), 7.33 (d, J=16.0 Hz, 1H), 6.60 (d, J=15.9 Hz, 1H), 2.42 (s, 4H), 2.24 (s, 3H) ppm.

(275) 4-(3-amino-4-methylphenyl)butan-2-one (55n): Compound 95 (0.40 mmol) was solubilized in 30 mL of MeOH, and 10% Palladium on charcoal (5 mg) was added. The reaction mixture was stirred under Hydrogen atmosphere for 12 h, then the mixture was filtered off on a celite pad and the solvent was evaporated at reduced pressure. Yield 99% .sup.1H NMR (400 MHz, CDCl.sub.3) 7.02-6.86 (m, 1H), 6.55-6.40 (m, 1H), 3.93 (s, 2H), 3.38 (s, 1H), 2.73 (d, J=6.8 Hz, 1H), 2.65 (dd, J=21.6, 14.4 Hz, 1H), 2.10 (s, 1H), 2.08 (s, 1H). MS (ESI) m/z 178.0 [M+H].sup.+.

Example 17

(276) ##STR00128##

(277) benzaldehyde oxime (98): Hydroxylamine hydrochloride (1103 mg, 15.8 mmol) was dissolved in water (10 mL) and neutralized with a 10% NaOHaq solution. A solution of 97 (2000 mg, 13.2 mmol) in ethanol was added slowly to this mixture with stirring at rt for 1 hr. After this time ethanol was evaporated at reduced pressure. Water was added and the rxn mixture was extracted with dichloromethane (340 mL). The combined organic phase was washed with brine and dried with anhydrous sodium sulfate. 98 was used for further reactions without additional purification. .sup.1HNMR (400 MHz, CDCl.sub.3-d): 8.25 8.23 (d, J=7.2 Hz, 2H), 8.23 (s, 1H), 7.75 (s, 1H), 7.73-7.72 (t, J=7.2 Hz, 2H) ppm. MS (ESI) m/z 164.9 [MH].sup.

(278) N-hydroxy-4-nitrobenzimidoyl chloride (99): 98 (100 mg, 0.60 mmol) was dissolved in dry DMF (2 mL) under nitrogen atmosphere. To this stirring solution, N-chlorosuccinimide was added (96.5 mg, 0.72 mmol). Initiation of the reaction was accelerated by use of UV light for 20 min. After 3 hrs the mixture was poured onto crushed ice, and extracted three times with Et.sub.2O. The organic layers were collected, dried over anhydrous Na.sub.2SO.sub.4 and the solvent was evaporated. 99 was used for further reactions without additional purification.

(279) 5-butyl-3-(4-nitrophenyl)isoxazole (100): 1-hexyne (28 L, 0.25 mmol), 99 (50 mg, 0.25 mmol), KHCO.sub.3 (119 mg, 1.08 mmol) were suspended in a 1:1 mixture of water and t-BuOH (1.5 mL each) in a 10 mL glass vial equipped with a small magnetic stirring bar. To this, was added sodium ascorbate (2 mg, 0.02 mmol) and copper(II) sulfate pentahydrate (2 mg, 0.02 mmol). The mixture was then heated for 7 min. at 80 C. under microwave irradiation, using an irradiation power of 300 W. After this time the solvents were partially removed, the residue was stirred with NH.sub.4Cl ss (10 mL), and NH.sub.4OH (0.5 mL) for 15 min, then extracted with EtOAc. The residue was finally purified on silica gel, to give final products (PE/EtOAc 98:2). Yield 76% .sup.1HNMR (400 MHz, CDCl.sub.3-d): 8.31-8.29 (d, J=8.4 Hz, 2H), 7.97-7.95 (d, J=8.4 Hz, 2H), 6.35 (s, 1H), 2.84-2.80 (t, J=7.2 Hz, 2H), 1.77-1.70 (m, 2H), 1.46-1.41 (q, J=7.2 Hz, 2H), 0.98-0.94 (t, J=7.2 Hz, 3H) ppm.

(280) 4-(5-butylisoxazol-3-yl)aniline (101): 99 (100 mg, 0.40 mmol) was dissolved in DCM and cooled to 0 C. Zinc dust (392 mg, 6 mmol) and AcOH (366 L) were added and the reaction mixture was stirred at rt for 30 min. After this time the mixture was filtered off on a celite pad. The pH was adjusted to 7 by addition of NaHCO.sub.3(ss), and the mixture was extracted several times. The organic layers were collected, washed with Brine and dried over anhydrous Na.sub.2SO.sub.4 Yield 70%. .sup.1HNMR (400 MHz, CDCl.sub.3-d): 7.59-7.57 (m, 2H), 6.72-6.71 (d, J=7.2 Hz, 2H), 6.18 (s, 1H), 3.84 (s, 2H), 2.77-2.73 (t, J=7.6 Hz, 3H), 1.74-1.67 (m, 2H), 1.46-1.37 (m, 2H), 0.96-0.93 (t, J=7.6 Hz, 3H) ppm. MS (ESI) m/z 216.9 [MH].sup.+

(281) 1-(4-(5-butylisoxazol-3-yl)phenyl)-3-(2-(trifluoromethyl)phenyl)urea (102): 100 (100 mg, 0.46 mmol) was added to a solution of the 1-(Trifluoromethyl)phenyl isocyanate 24 (85 L, 0.65 mmol) in anhydrous CH.sub.2Cl.sub.2 (10 mL) in one portion. The solution was stirred for 4 hours at r.t. under a nitrogen atmosphere. The solvent was removed, at reduced pressure and the residue purified by flash chromatography (PE/EtOAc 95:5) Yield 73% .sup.1HNMR (400 MHz, CDCl.sub.3-d): 7.99-7.97 (d, J=7.6 Hz, 2H), 7.71-7.69 (d, J=7.6 Hz, 2H), 7.58-7.56 (d, J=7.2 Hz, 2H), 7.51-7.18 (m, 2H), 7.03 (s, 2H), 2.78-2.77 (d, J=6.8 Hz, 2H), 1.71-1.61 (m, 2H), 1.42-1.40 (d, J=6.4 Hz, 2H), 0.96-0.87 (t, J=6.8 Hz, 3H) ppm .sup.13C-NMR (100 MHz, CDCl.sub.3-d): 174.66, 163.30, 152.83, 139.94, 136.25, 134.15, 133.10, 128.10, 126.20, 125.37, 124.86, 124.63, 124.22, 120.74, 98.30, 29.99, 26.83, 22.62, 13.94 ppm. MS (ESI) m/z 402.2 [MH].sup.

Example 18

(282) ##STR00129##

(283) N-hydroxy-4-nitrobenzimidamide (103): hdroxylamine hydrochloride (469 mg, 6.75 mmol) was dissolved in water and neutralized with NaOH 2N. A solution of 102 (500 mg, 3.37 mmol) in ethanol was added with continuous stirring. The reaction mixture was stirred at rt for 12 hrs, then was extracted with DCM. The combined organic phase was washed with brine and dried. Yield 88.3%.sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.26-8.24 (d, J=8.4 Hz, 2H), 7.82-7.80 (d, J=8.2 Hz, 2H), 4.89 (s, 2H), 1.57 (s, 1H) ppm. MS (ESI) m/z 181.9 [M+H]+MS (ESI) m/z 182.1 [M+H].sup.+

(284) 5-butyl-3-(4-nitrophenyl)-1,2,4-oxadiazole (104): EDC HCl (1587 mg, 8.28 mmol), HOBt (373 mg, 2.76 mmol) and DIPEA (1.44 mL), were dissolved in a 10:1 mixture of DCM and DMF (22 mL) at 0 C. Valeric acid (300 L, 8.28 mmol) was added, and the mixture was stirred under nitrogen atmosphere for 1 h at rt. After this time 103 (4.1 mmol) was added and the mixture was stirred at rt for 1 h, then at 110 C. for 12 h. After this time the solvent was removed at reduced pressure, and extracted with EtOAc. The organic phase was washed with 5% LiCl(aq) solution, and dried over Na.sub.2SO.sub.4. The residue was purified by flash chromatography on silica gel. (PE/EtOAc 9:1). Yield 73% .sup.1HNMR (400 MHz, CDCl.sub.3-d): 8.20-8.18 (d, J=8.4 Hz, 2H), 8.13-8.11 (d, J=8.8 Hz, 2H), 2.91-2.87 (t, J=7.6 Hz, 2H), 1.82-1.74 (m, 2H), 1.44-1.34 (m, 2H), 0.91-0.88 (t, J=7.6 Hz, 3H) ppm.

(285) 4-(5-butyl-1,2,4-oxadiazol-3-yl)aniline (105): 104 (95 mg, 0.38 mmol) was solubilized in a mixture of EtOH (30 mL) and water 2.5 mL. To this Iron powder (107.2 mg, 1.92 mmol) and NH.sub.4Cl (11 mg, 0.19 mmol) were added. The reaction mixture was heated at 80 C. and stirred for 30 min. After this time the reaction was warmed to rt and filtered on a celite pad. The mixture was concentrated and water (15 mL) was added, followed by extraction with EtOAc. The organic layers were washed with Brine and dried over Na.sub.2SO.sub.4. Yield 95% .sup.1H NMR (400 MHz, CDCl.sub.3-d): 7.84-7.83 (d, J=7.2 Hz, 2H), 6.70-6.68 (d, J=7.2 Hz, 2H), 3.82 (s, 2H), 2.90-2.86 (t, J=6.8 Hz, 2H), 1.82-1.79 (t, J=6.8 Hz, 2H), 1.43-1.41 (d, J=7.2 Hz, 2H), 0.95-0.92 (t, J=6.4 Hz, 3H) ppm.

(286) 1-(4-(5-butyl-1,2,4-oxadiazol-3-yl)phenyl)-3-(2-(trifluoromethyl)phenyl)urea (106): 105 (0.46 mmol) was added to a solution of the 1-(Trifluoromethyl)phenyl isocyanate 24 (85 L, 0.65 mmol) in anhydrous CH.sub.2Cl.sub.2 (10 mL) in one portion. The solution was stirred for 4 hours at r.t. under a nitrogen atmosphere. The solvent was removed, at reduced pressure and the residue purified by flash chromatography (PE/EtOAc 9:1) Yield 76% .sup.1HNMR (400 MHz, CDCl.sub.3-d): 7.58-7.56 (d, J=7.6 Hz, 2H), 7.44-7.41 (m, 3H), 7.25 (s, 1H), 7.18 (s, 1H), 7.08 (s, 1H), 1.86-1.82 (t, J=7.2 Hz, 2H), 1.48-1.42 (m, 2H), 0.96-0.94 (t, J=7.6 Hz, 3H) ppm .sup.13C-NMR (100 MHz, ACETONE-d.sub.6): 180.10, 152.51, 142.51, 136.56, 132.78, 127.87, 125.98, 125.32, 123.81, 120.98, 118.33, 25.69, 21.82, 13.03 ppm.

Example 19

(287) ##STR00130##

(288) ethyl 4-nitrobenzoate (108): 107 (200 mg, 1.19 mmol), was solubilized in a mixture of H.sub.2SO.sub.4 (4 mL) and EtOH (10 mL). The mixture was stirred at 100 C. for 1 h. After this time the solvent was partially evaporated at reduced pressure and the pH adjusted to 6 with NaHCO.sub.3. The reaction was extracted with EtOAc, washed with Brine and dried over Na.sub.2SO.sub.4. Yield: 90% .sup.1HNMR (400 MHz, CDCl.sub.3-d): 8.26-8.24 (d, J=8.8, 2H), 8.19-8.17 (d, J=8.8, 2H), 4.43-4.38 (m, 2H), 1.41-1.38 (t, J=7.2, 3H) ppm.

(289) 4-nitrobenzohydrazide (109): To a solution of 108 (180 mg, 0.92 mmol) in EtOH (20 mL), N.sub.2H.sub.4.H.sub.2O (236 L) was added. The resulting solution was heated to refluc for 48 h. After this time the mixture was warmed at rt, and the volatiles were removed in vacuo. The residue was crystallized in ACN. Yield 85% .sup.1HNMR (400 MHz, MeOD-d): 8.31-8.29 (d, J=8.8, 2H), 7.99-7.97 (d, J=8.8, 2H) ppm.

(290) 2-butyl-5-(4-nitrophenyl)-1,3,4-oxadiazole (110): A solution of valeraldehyde (58.7 L, 0.55 mmol) and 109 (100 mg, 0.55 mmol) in EtOH, was heated at reflux for 12 h. After this time, the solvent was removed at reduced pressure. The resulting residue was redissolved in DMSO (3 mL) and K.sub.2CO.sub.3 (228.04 mg, 1.65 mmol) and 12 (155.63 mg, 0.66 mmol) were added. The reaction mixture was stirred at 100 C. for 12 h. After completation of the reaction the mixture was cooled and treated with Na.sub.2S.sub.2O.sub.3, then extracted with EtOAc (325 mL), washed with Brine and dried over Na.sub.2SO.sub.4. The residue purified by flash chromatography. (PE/EtOAc 9:1). Yield: 70%: .sup.1HNMR (400 MHz, CDCl.sub.3-d): 8.35-8.33 (d, J=8.4 Hz, 2H), 8.22-8.20 (d, J=8.4 Hz, 2H), 2.97-2.93 (t, J=7.6 Hz, 2H), 1.86-1.82 (t, J=7.2 Hz, 2H), 1.49-1.44 (m, 2H), 0.99-0.95 (t, J=6.8 Hz, 3H) ppm.

(291) 4-(5-butyl-1,3,4-oxadiazol-2-yl)aniline (111): Compound 110 (0.40 mmol) was solubilized in 30 mL of MeOH, and 10% Palladium on charcoal (5 mg) was added. The reaction mixture was stirred under Hydrogen atmosphere for 1 h, then the mixture was filtered off on a celite pad and the solvent was evaporated at reduced pressure. Yield 99% Eluente. DCM/MeOH 98:2, Yield: 72%, .sup.1HNMR (400 MHz, CDCl.sub.3-d): 7.80-7.78 (d, J=8.4 Hz, 2H), 6.71-6.69 (d, J=8.8 Hz, 2H), 4.07 (s, 2H), 2.88-2.84 (t, J=7.6 Hz, 2H), 1.82-1.75 (m, 2H), 1.48-1.39 (m, 2H), 0.96-0.93 (t, J=7.6 Hz, 3H) ppm.

(292) 1-(4-(5-butyl-1,3,4-oxadiazol-2-yl)phenyl)-3-(2-(trifluoromethyl)phenyl)urea (112): Aniline 111 (31 mg, 0.14 mmol) was added to a solution of 2-(Trifluoromethyl)phenyl isocyanate (22 L, 0.15 mmol) in anhydrous CH.sub.2Cl.sub.2 (15 mL) in one portion. The solution was stirred for 9 hours at r.t. under a nitrogen atmosphere. The solvent was removed at reduced pressure and the residue purified on silica to furnish the final product as white solid. (Purification eluent: PE/EtOAc 7:3). Yield 71%, white solid. .sup.1HNMR (400 MHz, MeOD-d): 7.95-7.93 (d, J=8.4, 2H), 7.67-7.65 (d, J=8.8, 2H), 7.63-7.59 (m, 2H), 7.31-7.27 (m, 2H), 2.96-2.92 (d, J=7.6, 2H), 1.86-1.78 (m, 2H), 1.51-1.42 (m, 2H), 1.00-0.97 (t, J=7.2, 3H) ppm. .sup.13C-NMR (100 MHz, ACETONE-d.sub.6): 166.35, 164.11, 152.03, 142.81, 136.48, 132.79, 127.35, 125.90, 125.55, 123.65, 118.51, 29.30, 29.11, 28.92, 28.73, 28.54, 24.56, 21.82, 12.95 ppm.

Example 20

(293) ##STR00131##

(294) 4-nitrobenzohydrazide (109): To a solution of 108 (180 mg, 0.92 mmol) in EtOH (20 mL), N.sub.2H.sub.4.H.sub.2O (236 L) was added. The resulting solution was heated to refluc for 48 h. After this time the mixture was warmed at rt, and the volatiles were removed in vacuo. The residue was crystallized in ACN. Yield 85% .sup.1HNMR (400 MHz, MeOD-d): 8.31-8.29 (d, J=8.8, 2H), 7.99-7.97 (d, J=8.8, 2H) ppm.

(295) ethyl pentanoate (114): 113 (1000 mg, 9.79 mmol), was solubilized in a mixture of H.sub.2SO.sub.4 (4 mL) and EtOH (10 mL). The mixture was stirred at 100 C. for 3 h. After this time the solvent was partially evaporated at reduced pressure and the pH adjusted to 6 with NaHCO.sub.3. The reaction was extracted with EtOAc, washed with Brine and dried over Na.sub.2SO.sub.4. Yield 99%. .sup.1HNMR (400 MHz, CDCl.sub.3-d): 4.12-4.07 (q, J=7.2, 2H), 2.29-2.25 (t, J=8.0 Hz, 2H), 1.62-1.54 (m, 2H), 1.37-1.30 (q, J=8.0 Hz, 2H), 1.28-1.18 (t, J=8.0 Hz, 3H) ppm.

(296) pentanehydrazide (115): To a solution of 114 (420 mg, 3.22 mmol) in EtOH (20 mL), N.sub.2H.sub.4.H.sub.2O (783 L) was added. The resulting solution was heated to refluc for 12 h. After this time the mixture was warmed at rt, and the volatiles were removed in vacuo. 115 was used for further reactions without additional purification. Yield: 99% .sup.1HNMR (400 MHz, CDCl.sub.3-d): 7.25 (s, 1H), 2.15-2.119 (d, J=7.6, 2H), 1.64-1.57 (m, 2H), 1.37-1.28 (m, 2H), 0.92-0.88 (t, J=7.2, 3H) ppm.

(297) 3-butyl-5-(4-nitrophenyl)-4H-1,2,4-triazole (117): A 30% solution of MeONa (2.36 mmol) in anhydrous Methanol, was added dropwise to a solution of 116 (3.98 mmol) in CH.sub.3OH. The reaction mixture was stirred at rt for 1 h. The pH was adjusted to 6 with CH.sub.3COOH at 0 C. then 115 (4.3 mmol) was added. The rxn was stirred at rt for 2 h, then the solvent was removed at reduced pressure. Toluene (10 mL) was added and the reaction was heated at reflux with a Dean-Stark trap for 12 h. After this time the reaction was cooled and water and EtOAc were added. The mixture was stirred at rt for 30 min, then extracted, washed with Brine and dried over Na.sub.2SO.sub.4. The solvent was removed at reduced pressure and the residue was purified by flash chromatography. (PE/EtOAc 6:4). Yield 60%, .sup.1H NMR (400 MHz, CDCl.sub.3-d: 8.37-8.35 (d, J=8.4, 2H), 8.29-8.24 (d, J=7.6, 2H), 1.84-1-76 (m, 2H), 1.46-1.39 (m, 2H), 0.98-0.946 (t, J=7.2 Hz, 3H) ppm. .sup.13C-NMR (100 MHz, ACETONE-d.sub.6): 160.05, 159.25, 148.07, 136.95, 127.13, 124.00, 77.39, 77.08, 76.76, 29.98, 26.36, 22.29, 13.58 ppm.

(298) 4-(5-butyl-4H-1,2,4-triazol-3-yl)aniline (118): 117 (0.40 mmol) was solubilized in 30 mL of MeOH, and 10% Palladium on charcoal (5 mg) was added. The reaction mixture was stirred under Hydrogen atmosphere for 1 h, then the mixture was filtered off on a celite pad and the solvent was evaporated at reduced pressure. The residue was purified by flash chromatography (PE/EtOAc/TEA 6:4:0.5). Yield 70% .sup.1HNMR (400 MHz, CDCl.sub.3-d): 7.77-7.75 (d, J=6.8 Hz, 2H), 6.68-6.66 (d, J=6.8 Hz, 2H), 4.13 (s, 1H), 2.77-2.75 (d, J=7.6 Hz, 2H), 1.72-1.71 (d, J=7.2 Hz, 2H), 1.38-1.34 (d, J=8.0 Hz, 2H), 0.91-0.88 (m, 3H) ppm.

(299) 1-(4-(5-butyl-4H-1,2,4-triazol-3-yl)phenyl)-3-(2-(trifluoromethyl)phenyl)urea (119): Aniline 118 (25 mg, 0.11 mmol) was added to a solution of 2-(Trifluoromethyl)phenyl isocyanate (18 L, 0.11 mmol) in anhydrous CH.sub.2Cl.sub.2 (15 mL) in one portion. The solution was stirred for 12 hours at r.t. under a nitrogen atmosphere. The solvent was removed at reduced pressure and the residue purified on silica to furnish the final product as white solid. (Purification eluent: PE/EtOAc 7:3). Yield 70%, white solid. .sup.1HNMR (400 MHz, MeOD-d): 7.95-7.89 (m, 4H), 7.66-7.56 (m, 4H), 7.29-7.25 (m), 2.81-2.77 (d, J=7.6 Hz, 2H), 1.79-1.72 (m, 2H), 1.45-1.36 (m, 2H), 0.98-0.94 (t, J=7.6 Hz, 3H) ppm. .sup.13C-NMR (100 MHz, MeOD-d.sub.6): 153.58, 146.64, 140.81, 135.86, 132.40, 126.77, 126.01, 125.67, 124.01, 121.78, 121.44, 118.53, 30.00, 29.31, 25.76, 21.88, 12.61 ppm.

Example 21

(300) ##STR00132##

(301) 4-nitrobenzoyl chloride (120): 107 (719.8 mg, 4.30 mmol), was stirred with 1 mL of anhydrous SOCl.sub.2, at 100 C., for 1 h. The excess of SOCl.sub.2 was removed by distillation. 120 was used for further reactions without additional purification.

(302) 4-nitro-N-pentanoylbenzohydrazide (121): A solution of 120 (500 mg, 4.30 mmol) and DMAP (525 mg, 4.30 mmol) in dry DCM (5 mL) was added dropwise to a solution of 120 in anhydrous DCM. The resulting mixture was stirred at rt on. The solvent was removed at reduced pressure and the residue purified by flash chromatography (DCM/MeOH/TEA 98:2:0.5), Yield: 67%, .sup.1H NMR (400 MHz, MeOD-d): 8.34-8.31 (d, J=8.8, 2H), 8.08-8.06 (d, J=8.8, 2H), 2.34-2.30 (q, J=7.2, 2H), 1.71-1.57 (q, 2H), 1.47-1.35 (t, J=7.7 Hz, 3H) ppm.

(303) 2-butyl-5-(4-nitrophenyl)-1,3,4-thiadiazole (122): Lawesson's reagent (458 mg, 1.31 mmol) was added to a stirring solution of 121 in anhydrous dioxane (20 mL). The reaction mixture was stirred at 80 C. for 24 h. Dioxane was removed under reduced pressure, and the residue obtained was dissolved in water. The pH was basified to 9 by adding of NaHCO.sub.3(aq) and the organic phases were washed with brine and dried over Na.sub.2SO.sub.4. The residue was purified by flash chromatography (PE/EtOAc 8:2), Yield 60% .sup.1HNMR (400 MHz, CD.sub.3OD): 8.39-8.37 (d, J=8.8 Hz, 2H), 8.26-8.24 (d, J=8.8 Hz, 2H), 3.22-3.18 (t, J=7.6 Hz, 2H), 1.87-1.79 (m, 2H), 1.51-1.42 (m, 2H), 0.98-0.94 (t, J=7.2 Hz, 3H) ppm.

(304) 4-(5-butyl-1,3,4-thiadiazol-2-yl)aniline (123): 122 (58 mg, 0.22 mmol) was solubilized in a mixture of EtOH (30 mL) and water 2.5 mL. To this Iron powder (62 mg, 1.1 mmol) and NH.sub.4Cl (6 mg, 0.11 mmol) were added. The reaction mixture was heated at 80 C. and stirred for 30 min. After this time the reaction was warmed to rt and filtered on a celite pad. The mixture was concentrated and water (15 mL) was added, followed by extraction with EtOAc. The organic layers were washed with Brine and dried over Na.sub.2SO.sub.4. Yield 75% .sup.1HNMR (400 MHz, CDCl.sub.3-d): 7.72-7.70 (d, J=8.0, 2H) 6.70-6.68 (d, J=8.0, 2H), 3.96 (s, 2H), 3.10-3.06 (t, J=8.0, 2H), 1.82-1.75 (q, J=7.6 Hz, 2H), 1.49-1.40 (q, J=7.6 Hz, 2H), 0.97-0.93 (t, J=8.0 Hz, 3H) ppm. MS (ESI) m/z 234.1 [M+H].sup.+

(305) 1-(4-(5-butyl-1,3,4-thiadiazol-2-yl)phenyl)-3-(2-(trifluoromethyl)phenyl)urea (124): Aniline 123 (25 mg, 0.11 mmol) was added to a solution of 2-(Trifluoromethyl)phenyl isocyanate (17 L, 0.11 mmol) in anhydrous CH.sub.2Cl.sub.2 (15 mL) in one portion. The solution was stirred for 12 hours at r.t. under a nitrogen atmosphere. The solvent was removed at reduced pressure and the residue purified on silica to furnish the final product as white solid. (Purification eluent: PE/EtOAc 7:3). Yield 68%, white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d) 7.57 (m 5H), 7.31-7.22 (m, 2H), 7.18 (dd, J=7.5, 1.6 Hz, 1H), 6.97 (td, J=7.5, 1.6 Hz, 1H), 4.18 (s, 1H), 2.75 (t, J=5.5 Hz, 2H), 1.65 (dq, J=7.7, 5.6 Hz, 2H), 1.46-1.32 (m, 2H), 1.32-1.07 (m, 3H) ppm.

Example 22

(306) ##STR00133##

(307) 3-(Chlorosulfonyl)benzoic acid, (126): Chlorosulfonic acid (2 mL, 300.4 mmol) was added to 125, (500 mg, 40.9 mmol) and the mixture was stirred at 120 C. for 2 h. After this time the mixture was added dropwise to a mixture of EtOAc (200 mL) and crushed ice. The resulting precipitate was collected, dissolved in ethyl acetate, washed with water (325 mL) and Brine, dried over Na.sub.2SO.sub.4, and the solvent was removed under reduced pressure. .sup.1H-NMR (400 MHz, DMSO-d6): =8.80 (t, J=1.4 Hz, 1H), 8.40 (m 1H), 8.19 (m, 1H), 7.69 (t, J=7.5 Hz, 1H). ppm.

(308) 3-(N-(2-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid (127): To a stirred solution of 2-trifluoromethyl-phenylaniline (1 eq.) in 5 mL of anhydrous pyridine, was added sulphonyl chloride 126 (1.1 eq) at 0 C. The corresponding solution was stirred at r.t. under nitrogen atmosphere, for 5 h. After completion of the reaction the mixture was acidified with 1N HCl, the aqueous phase was extracted with several times and the combined organic phases were dried (Na.sub.2SO.sub.4) and concentrated. (PE-AcOEt 95:5). Yield 75%, white solid. .sup.1H NMR (400 MHz, CDCl.sub.3-d): 9.44 (s, 1H), 8.72 (s, 1H), 8.39 (s, 1H), 8.23 (s, 1H), 7.71 (s, 1H), 7.35 (s, 1H), 7.20 (s, 1H), 6.82 (s, 1H), 6.71 (s, 1H), 6.08 (s, 1H). ppm. MS (ESI): m/z 344 [MH].sup..

(309) ethyl 3-(N-(2-(trifluoromethyl)phenyl)sulfamoyl)benzoate (128): 127 (200 mg, 1.19 mmol), was solubilized in a mixture of H.sub.2SO.sub.4 (4 mL) and EtOH (10 mL). The mixture was stirred at 100 C. for 1 h. After this time the solvent was partially evaporated at reduced pressure and the pH adjusted to 6 with NaHCO.sub.3. The reaction was extracted with EtOAc, washed with Brine and dried over Na.sub.2SO.sub.4. Yield: 87% .sup.1H NMR (400 MHz, CDCl.sub.3-d): 8.41 (s, 1H), 8.20 (d, J=7.8 Hz, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.60-7.44 (m, 2H), 7.25 (t, J=7.7 Hz, 1H), 6.74 (t, J=7.9 Hz, 1H), 4.36 (q, J=7.6 Hz, 2H), 1.38 (t, J=7.5 Hz, 3H). ppm.

(310) 3-(hydrazinecarbonyl)-N-(2-(trifluoromethyl)phenyl)benzenesulfonamide (129): To a solution of 128 (90 mg, 0.24 mmol) in EtOH (20 mL), N.sub.2H.sub.4.H.sub.2O (58 L) was added. The resulting solution was heated to refluc for 48 h. After this time the mixture was warmed at rt, and the volatiles were removed in vacuo. The residue was crystallized in ACN. Yield 85% .sup.1HNMR (400 MHz, Acetone-d.sub.6): 7.39 (dd, J=7.5, 1.4 Hz, 1H), 7.18 (ddd, J=19.2, 12.6, 1.0 Hz, 2H), 6.84 (td, J=7.5, 1.4 Hz, 1H), 6.71 (dd, J=7.5, 1.5 Hz, 1H), 6.07-6.01 (m, 2H), 5.79 (d, J=2.0 Hz, 1H), 5.64 (s, 1H), 2.05 (s, 1H), 2.00 (d, J=0.8 Hz, 3H), 1.66 (s, 1H). ppm.

(311) 2-butyl-5-(4-nitrophenyl)-1,3,4-oxadiazole (130): A solution of valeraldehyde (15 L, 0.14 mmol) and 129 (50 mg, 0.14 mmol) in EtOH, was heated at reflux for 12 h. After this time, the solvent was removed at reduced pressure. The resulting residue was redissolved in DMSO (3 mL) and K.sub.2CO.sub.3 (58 mg, 0.42 mmol) and 12 (43 mg, 0.16 mmol) were added. The reaction mixture was stirred at 100 C. for 12 h. After completation of the reaction the mixture was cooled and treated with Na.sub.2S.sub.2O.sub.3, then extracted with EtOAc (325 mL), washed with Brine and dried over Na.sub.2SO.sub.4. The residue purified by flash chromatography. (PE/EtOAc 8:2). Yield: 73% .sup.1HNMR (400 MHz, CDCl.sub.3-d): 8.21 (s, 2H), 8.04 (s, 2H), 7.86 (s, 2H), 7.65 (s, 2H), 7.33 (s, 2H), 7.17 (s, 2H), 6.81 (s, 2H), 6.69 (s, 2H), 6.19 (s, 2H), 2.73-2.68 (m, 4H), 1.67-1.62 (m, 3H), 1.40-1.35 (m, 3H), 1.01-0.96 (m, 6H). ppm. .sup.13C NMR (100 MHz, CDCl.sub.3-d) 166.44, 162.20, 144.51, 139.07, 135.27, 133.84, 132.13, 131.76, 128.46, 128.22, 127.97, 127.75 123.87, 27.52, 26.97, 22.18, 14.02 ppm.

Example 23

(312) ##STR00134##

(313) hydroxy-3-(N-(2-(trifluoromethyl)phenyl)sulfamoyl)benzimidamide (133): hydroxylamine hydrochloride (469 mg, 6.75 mmol) was dissolved in water and neutralized with NaOH 2N. A solution of 132 (3.37 mmol) in ethanol was added with continuous stirring. The reaction mixture was stirred at rt for 12 hrs, then was extracted with DCM. The combined organic phase was washed with brine and dried. Yield 99% .sup.1HNMR (400 MHz, Acetone): 8.23 (s, 1H), 7.98 (d, J=7.7 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.58 (d, J=7.3 Hz, 2H), 7.47 (d, J=8.1 Hz, 1H), 7.39 (t, J=7.2 Hz, 1H). MS (ESI) m/z 362.1 [M+H].sup.+

(314) 3-(5-butyl-1,2,4-oxadiazol-3-yl)-N-(2-(trifluoromethyl)phenyl)benzenesulfonamide (134): EDC HCl (1587 mg, 8.28 mmol), HOBt (373 mg, 2.76 mmol) and DIPEA (1.44 mL), were dissolved in a 10:1 mixture of DCM and DMF (22 mL) at 0 C. Valeric acid (300 L, 8.28 mmol) was added, and the mixture was stirred under nitrogen atmosphere for 1 h at rt. After this time 133 (4.1 mmol) was added and the mixture was stirred at rt for 1 h, then at 110 C. for 12 h. After this time the solvent was removed at reduced pressure, and extracted with EtOAc. The organic phase was washed with 5% LiCl(aq) solution, and dried over Na.sub.2SO.sub.4. The residue was purified by flash chromatography on silica gel. (PE/EtOAc 7:3). Yield 73% .sup.1H NMR (400 MHz, Acetone) 8.29 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.70-7.53 (m, 2H), 7.43 (dd, J=15.2, 7.8 Hz, 2H), 6.47 (s, 2H), 2.47 (t, J=7.4 Hz, 2H), 1.63 (dd, J=15.1, 7.5 Hz, 2H), 1.38 (dd, J=14.9, 7.5 Hz, 2H), 0.92 (t, J=7.4 Hz, 3H). ppm. .sup.13C NMR (101 MHz, Acetone) 169.93, 154.59, 141.46, 134.45, 133.19, 130.93, 129.43, 128.77, 127.07, 126.88, 126.64, 125.30, 32.17, 26.90, 22.02, 13.12. MS (ESI) m/z 426.3 [M+H].sup.+

Example 24

(315) In Vitro ADME Studies

(316) ADME properties of compounds are actually of primary importance. Poor solubility and poor permeability are among the main causes of failure during drug-development. In general, it is important try to find a good balance between lipid bilayer permeability, that affect gastrointestinal absorption by passive diffusion after oral dosing, and solubility. For these reasons, physicochemical properties of our compounds were predicted, starting from the first phases, using QikProp (QP) prediction program (QikProp, version 3.3, Schrdinger, LLC, New York, N.Y., 2010).

(317) A few in vitro experiments were conducted to quickly establish the absorption/stability of drug candidates in the early phase: aqueous solubility, parallel artificial membrane permeability (PAMPA) assay and human liver microsome (HLM) stability determination.

(318) Materials and Methods

(319) Chemicals. All solvents, reagents, were from Sigma-Aldrich Srl (Milan, Italy). Dodecane was purchased from Fluka (Milan, Italy). Pooled Male Donors 20 mg mL.sup.1 HLM were from BD Gentest-Biosciences (San Jose, Calif.). Milli-Q quality water (Millipore, Milford, Mass., USA) was used. Hydrophobic filter plates (MultiScreen-IP, Clear Plates, 0.45 m diameter pore size), 96-well microplates, and 96-well UV-transparent microplates were obtained from Millipore (Bedford, Mass., USA).

(320) Parallel Artificial Membrane Permeability Assay (PAMPA). Donor solution (0.5 mM) was prepared by diluting 1 mM dimethylsulfoxide (DMSO) compound stock solution using phosphate buffer (pH 7.4, 0.025 M). Filters were coated with 5 L of a 1% (w/v) dodecane solution of phosphatidylcholine prepared from CHCl.sub.3 solution 10% w/v, for intestinal permeability. Donor solution (150 L) was added to each well of the filter plate. To each well of the acceptor plate were added 300 of solution (50% DMSO in phosphate buffer). All compounds were tested in three different plates on different days. The sandwich was incubated for 5 h at room temperature under gentle shaking. After the incubation time, the plates were separated, and samples were taken from both receiver and donor sides and analyzed using LC with UV detection at 280 nm.

(321) LC analysis were performed with a Varian Prostar HPLC system (Varian Analytical Instruments, USA) equipped with a binary pump with a manual injection valve and model Prostar 325 UV-VIS Detector. Chromatographic separations were conducted using a Polaris C18-A column (150-4.6 mm, 5 m particle size) at a flow rate of 0.8 mL min.sup.1 with a mobile phase composed of 60% ACN/40% H.sub.2O

(322) Permeability (Papp) for PAMPA was calculated according to the following equation, obtained from Wohnsland and Faller and Sugano et al. equation with some modification in order to obtain permeability values in cm s.sup.1,

(323) $P_{app} = \frac{V_{D} V_{A}}{(V_{D} + V_{A}) At} - \ln (1 - r)$

(324) where V.sub.A is the volume in the acceptor well, V.sub.D is the volume in the donor well (cm.sup.3), A is the effective area of the membrane (cm.sup.2), t is the incubation time (s) and r the ratio between drug concentration in the acceptor and equilibrium concentration of the drug in the total volume (V.sub.D+V.sub.A). Drug concentration is estimated by using the peak area integration.

(325) Membrane retentions (%) were calculated according to the following equation:

(326) $% MR = \frac{[r - (D + A)] 100}{Eq}$

(327) where r is the ratio between drug concentration in the acceptor and equilibrium concentration, D, A, and Eq represented drug concentration in the donor, acceptor and equilibrium solution, respectively.

(328) Water Solubility Assay. Each solid compound (1 mg) was added to 1 mL of water. The samples were shaked in a shaker bath at room temperature for 24-36 h. The suspensions were filtered through a 0.45 m nylon filter (Acrodisc), and the solubilized compound determined by LC-MS-MS assay. For each compound the determination was performed in triplicate.

(329) For the quantification was used an LC-MS system consisted of a Varian apparatus (Varian Inc) including a vacuum solvent degassing unit, two pumps (212-LC), a Triple Quadrupole MSD (Mod. 320-LC) mass spectrometer with ES interface and Varian MS Workstation System Control Vers. 6.9 software. Chromatographic separation was obtained using a Pursuit C18 column (502.0 mm) (Varian) with 3 m particle size and gradient elution: eluent A being ACN and eluent B consisting of water. The analysis started with 0% of eluent A, which was linearly increased up to 70% in 10 min, then slowly increased up to 98% up to 15 min. The flow rate was 0.2 mL min.sup.1 and injection volume was 5 L. The instrument operated in positive mode and parameters were: detector 1850 V, drying gas pressure 25.0 psi, desolvation temperature 300.0 C., nebulizing gas 40.0 psi, needle 5000 V and shield 600 V. Nitrogen was used as nebulizer gas and drying gas. Collision induced dissociation was performed using Argon as the collision gas at a pressure of 1.8 mTorr in the collision cell.

(330) Microsomal Stability Assay. Each compound in DMSO solution was incubated at 37 C. for 60 min in 125 mM phosphate buffer (pH 7.4), 5 of human liver microsomal protein (0.2 mg mL.sup.1), in the presence of a NADPH-generating system at a final volume of 0.5 mL (compound final concentration, 50 M); DMSO did not exceed 2% (final solution). The reaction was stopped by cooling on ice and adding 1.0 mL of acetonitrile. The reaction mixtures were then centrifuged, and the parent drug and metabolites were subsequently determined by LC-UV-MS.

(331) Chromatographic analysis was performed with an Agilent 1100 LC/MSD VL system (G1946C) (Agilent Technologies, Palo Alto, Calif.) constituted by a vacuum solvent degassing unit, a binary high-pressure gradient pump, an 1100 series UV detector, and an 1100 MSD model VL benchtop mass spectrometer.

(332) Chromatographic separation was obtained using a Varian Polaris C18-A column (150-4.6 mm, 5 m particle size) and gradient elution: eluent A being ACN and eluent B consisting of water. The analysis started with 2% of eluent A, which was rapidly increased up to 70% in 12 min, then slowly increased up to 98% in 20 min. The flow rate was 0.8 mL min.sup.1 and injection volume was 20 L.

(333) The Agilent 1100 series mass spectra detection (MSD) single-quadrupole instrument was equipped with the orthogonal spray API-ES (Agilent Technologies, Palo Alto, Calif.). Nitrogen was used as nebulizing and drying gas. The pressure of the nebulizing gas, the flow of the drying gas, the capillary voltage, the fragmentor voltage, and the vaporization temperature were set at 40 psi, 9 L/min, 3000 V, 70 V, and 350 C., respectively. UV detection was monitored at 280 nm. The LC-ESI-MS determination was performed by operating the MSD in the positive ion mode. Spectra were acquired over the scan range m/z 100-1500 using a step size of 0.1 u. The percentage of not metabolized compound was calculated by comparison with reference solutions.

(334) TABLE-US-00004 TABLE 3 ADME properties of selected compounds PAMPA Papp *10.sup.6 QP (cm/s) Pred. Cmpd GI Aq. Solub. Log ID Structure (RM %) (g/mL) LogS S 20a embedded image 2.86 (19.1) 0.135 7.05 6.4 20b 1.93 (26.7) <0.001 <8.6 <6.7 21b 2.51 (59.1) <0.001 <8.6 7.3 81 7.22 (30.4) 80.11 6.4 7.3 22a 7.47 (23.9) 0.107 7.43 7.1 22b 0 7.41 (24.8) 0.002 <8.6 7.5 49 7.57 (24.8) <0.001 <8.5 5.74 20f 0.69 (7.4) 26.27 4.3 5.12 64e 0.68 (0) 1.37 5.57 5.47 68c embedded image 0.44 (0) 45.35 4.26 4.7

(335) TABLE-US-00005 TABLE 4 Metabolic stability of selected compounds Cmpd Sability ID Structure % 20a embedded image 99 81 94 49 95.6 64d 99 64e 98 68e 0 95.7

Example 25

(336) Biology

(337) Enzymatic Assays

(338) Helicase Assays

(339) The helicase activity of DDX3 wt was monitored by measuring the conversion of a double stranded (ds) RNA (labelled at the 5-end of one strand with a 6-FAM fluorescent) into single stranded (ss) nucleic acid. A final concentration of 25 nM RNA substrate was used in the experiments, unless otherwise stated. Reactions were performed in 50 mM TrisHCl pH 7.5, 1 mM DTT, 0.2 mg/ml BSA, 5% glycerol and 100 M ATP, 10 mM MgCl.sub.2 at 37 C. degrees for 10 and stopped by adding EDTA 50 mM pH 8. Products were separated through non-denaturating 8% PAGE at 5 W for 4 hours in TBE buffer at 4 C. Substrates and products were quantified by laser scanning densitometry (Thyphoon-TRIO, GE Healthcare).

(340) Proteins

(341) Human recombinant DDX3 was cloned, expressed and purified as described (Franca et al. Proteins 2007, 67, 1128-37).

(342) Antiviral Assays

(343) In Vitro Antiviral Activity (EC.sub.50) and Cytotoxicity (CC.sub.50) of Dengue Virus (DENY) and West Nile Virus (WNV).

(344) Around 10.sup.4 Huh7 cells (provided by Apath, LLC) cultured in Dulbecco's Modified Eagle Medium (DMEM) (Invitrogen, Carlsbad, Calif.) supplemented with 10% fetal bovine serum, 1% nonessential amino acids, 100 units/ml penicillin and 100 units/ml streptomycin (DMEM complete) per well were infected for 1 h with Dengue virus type 2 (DENV-2; New Guinea-C Strain, NCPV ref 0006041v) or West Nile virus New York 99 strain (WNV-NY99; NCPV ref 0209291v) at MOI (multiplicity of infection) of 0.5 in 96 well plates in. After washing viral input, 10 fold serial dilutions of DMSO control or DDX3 inhibitors were immediately added in duplicates to the corresponding wells together with fresh DMEM complete medium (final concentrations of 100, 10, 1, 0.1 and 0.01 M). 48 h after initial infection, cells were fixed with 4% PFA and immunostained against the viral E protein (envelope) using specific Anti E protein primary antibodies (Anti-DENV: Abcam Cat. Num. ab41349; Anti-WNV: Abcam Cat. Num. ab156843) and an AlexaFLuor488 secondary antibody (Invitrogen, Cat. Num. A11029). DAPI was used for nuclei staining. Plates were analyzed with the ImageXpress automated microscope, using the 20 Plan Fluor objective. The microscope was set for two channels (FITC and DAPI). Between 4 and 9 images were taken per well per condition at arbitrary objective fields. Between 500 and 1000 images were analysed using the CellProfiler Software (Broad Institute of MIT, http://www.cellprofiler.org/). Images were thresholded for background subtraction and target fluorescent dot sizes and intensities were analysed. Positive green counts and nuclei blue counts were estimated per image per condition.

(345) Relative % infectivity and toxicity for each compound was estimated by normalizing the number of green signals (positive counts) and blue signals (nuclei counts) to DMSO treated controls, respectively. EC50 and CC50 values were calculated in GraphPad (http://www.graphpad.com/) by applying a nonlinear regression with log dose vs. normalized response to the CellProfiler data.

(346) Evaluation of the In Vitro Antiviral Activity (EC.sub.50) and Cytotoxicity (CC.sub.50) in the HCV Replicon System.

(347) Antiviral activity was carried out in white-clear bottom 96-well plates, and cytotoxicity assays were performed in clear 96-well plates. LucUbiNeo-ET Cells were seeded at a density of 10.sup.4/well in 100 L D-MEM without selection of antibiotics. After 24 h, nine fold serial dilution of compounds, with 3 replicates at each dilution, were prepared in D-MEM and added to the appropriate wells, yielding concentrations of 125 to 0,00032 g/mL in a final volume of 100 L of D-MEM. After 2 days of incubation, the inventors determined the antiviral activity (EC.sub.50) by quantifying the luciferase with the BriteLite Plus luciferase (Perkin Elmer). Briefly, LucUbiNeo-ET cells were harvested with the addition of 50 L of luciferase per well, and after 2 minutes of shaking, the light was read in a Luminometer Fluoroskan Ascent FL.

(348) Toxicity (CC.sub.50) was analysed in the Lunet/HuH7 cells by the addition of 10 L of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) per well. After 4 h of incubation at 37 C. in a humidified atmosphere with 5% CO.sub.2, the amount of formazan produced was quantified spectrophotometrically at 550/620 nm (C. Pannecouque et al, Nature protocol 2008; 3 (3): 427-434). The EC.sub.50 and CC.sub.50 values were calculated for each compound in GraphPad by applying a non-linear regression with log dose vs. normalized response to the CellProfiler data. These assays were done in duplicate.

(349) Evaluation of the In Vitro Antiviral Activity (EC.sub.50) and Cytotoxicity (CC.sub.50) in the HCV Infectious Cell Culture System.

(350) Naive Huh-7.5/RFP(TagRFP)-NLS-IPS/mitoEGFP cells were seeded in clear 96-well plates the previous day at a concentration of 6400 cells/well. The next day, cells were infected with the HCV chimera Jc1 (genotype 2a) infectious supernatant at a multiplicity of infection (MOI) of 0.02. After 24 h, the cells were washed with PBS and the medium was replaced with complete growth medium with or without compounds. Nine fold serial dilution of compounds, with 3 replicates at each dilution, were prepared in D-MEM and added to the appropriate wells, yielding concentrations of 125 to 0,00032 g/mL in a final volume of 100 L of D-MEM. After 2 days of incubation, the cultures were immunostained for NS5A 9E10 monoclonal antibody as described by Lindenbach (Lindenbach B. D. et al. Complete Replication of Hepatitis C Virus in Cell Culture. Science 2005; 309: 623-626). Single HCV NS5A+ cells were manually counted for each well.

(351) Toxicity (CC.sub.50) was analysed in the nave Huh-7.5/RFP(TagRFP)-NLS-IPS/mitoEGFP cells by the addition of 10 L of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) per well. After 4 h of incubation at 37 C. in a humidified atmosphere with 5% CO.sub.2, the amount of formazan produced was quantified spectrophotometrically at 550/620 nm (C. Pannecouque et al, Nature protocol 2008; 3 (3): 427-434). The EC.sub.50 and CC.sub.50 values were calculated for each compound in GraphPad by applying a non-linear regression with log dose vs. normalized response to the CellProfiler data. These assays were done in duplicate.

(352) Evaluation of the In Vitro Antiviral Activity (EC.sub.50) and Cytotoxicity (CC.sub.50) in the HIV Infectious Cell Culture System.

(353) HeLa cell viability in the presence of the compounds has been determined by standard MTT assays. The susceptibility of HIV-1 recombinant strains to drugs was performed as previously reported (Paolucci et al., 2004). In detail, 0.5 g of each HIV-1 plasmid construct was transfected into CD4+ HeLa cells by using the lipofectin reagent, according to the recommendations of the manufacturer (Invitrogen, Groningen, The Netherlands). After 3 days of incubation at 37 C., the cell supernatants, which contained reconstituted viable recombinant viruses, were collected. Quantification of the newly produced recombinant strains was obtained by determination of the HIV RNA copy number in the cell culture supernatants. In detail, transfected HeLa CD4+ cell culture supernatants containing 110.sup.9/mL RNA copies were used to infect aliquots of 2010.sup.6 phytohemagglutinin-stimulated peripheral blood mononuclear cells (PBMC) obtained from HIV-seronegative blood donors. After 4 h of incubation, supernatants were removed and infected PBMC were incubated at 37 C. in 10 mL of RPMI 1640 medium (Eurobio, Les Ulis Cedex B, France) supplemented with 20% fetal calf serum (Life Technologies, Ltd., Paisley, UK), 2 mM Lglutamine, 100 U/mL penicillin, 100 g/mL streptomycin, 50 U/mL interleukin-2 (Roche Diagnostics, Mannheim, Germany), 5 g/mL hydrocortisone (Sigma Chemical Co., St. Louis, Mass.) and with fourfold dilutions of antiretroviral drugs. No-drug control for each drug dilution was included in each assay. The HIV-1 RNA in the cell culture supernatant was quantified after 72 h post infection. Recombinant HIV-1 strains from treatment-naive patients were assayed. The degree of inhibition of viral replication was measured by determining the HIV-1 RNA level in the supernatants of cell cultures and was expressed as the fold increase in the 50% inhibitory concentrations (IC.sub.50) for resistant recombinant HIV-1 variants, compared with the IC.sub.50 for the wild type recombinant variant. Each test was performed in triplicate.

(354) Toxicity (CC.sub.50) was analysed in human primary PBMCs. Increasing doses of the tested compounds were added to 210.sup.6 cells. Culture medium supplemented with fresh compound was replaced every 24 hours. After 72 hours of continuous exposure of the cells to the compounds at 37 C., cell viability was measured with the CellTiter 96 (Promega) viability assay, which contains MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] and an electron coupling reagent (phenazine ethosulfate). Assays are performed by adding 20 L of the Cell Titer 96 reagent directly to culture wells, incubating for 4 hours and then recording absorbance at 490 nm with a 96-well plate reader. The quantity of formazan product as measured by the amount of 490 nm absorbance is directly proportional to the number of living cells in culture. Determinations for each compound dose were in quadruplicate. The CC.sub.50 values were calculated from dose-response curves using the mean values of each set of determinations.

(355) Evaluation of the In Vitro Antiviral Activity (EC.sub.50) and Cytotoxicity (CC.sub.50) in the JEV Infectious Cell Culture System.

(356) Baby hamster kidney (BHK)-21 cells (C-13, American Type Culture Collection) were maintained in Dulbecco's minimal essential medium (Invitrogen) supplemented with 10% fetal calf serum (FCS) (GIBCO), penicillin (100 g/ml) and streptomycin (100 U/ml) at 37 C. and 5% CO.sub.2. JEV strain (NJ2008, GenBank Accession ID: GQ918133 was propagated in BHK-21 cells, the viral titer was determined by plaque formation assay in BHK-21 cells. In first experiment the drugs (20 M) were first incubated with the cells for 3 h, then the cells were washed three times with PBS (10 mM Na.sub.2HPO.sub.4, 2 mM KH.sub.2PO.sub.4, pH7.4, 137 mM NaCl, 2.7 mM KCl) and then the drugs (20 M) were inoculated simultaneously with the virus (MOI=0.01) for 2 hat 37 C. The cells were washed with PBS for three times and the drugs (20 M) were added back to the cells with the same concentration (20 M, diluted with 2% FCS DMEM). The cells were cultured for 48 h. The supernatant was harvested, diluted and inoculated in BHK-21 cells (1.2106 cells/well) in a 6-well plate for 2 h at 37 C. The excess virus inocula were removed by rinsing the wells with PBS for three times. Subsequently, overlay medium (2% low melting-point agarose with DMEM medium containing 2% FBS) was added to each well and the plates were further incubated at 37 C. with 5% CO.sub.2 for 3 days. The cells were stained with 0.5% crystal violet. Determinations for each compound dose were in quadruplicate. The CC.sub.50 values were calculated from dose-response curves using the mean values of each set of determinations.

(357) Evaluation of the In Vitro Antiviral Activity (EC.sub.50) in the PRRSV (Porcine Reproductive and Respiratory Syndrome Virus) Infectious Cell Culture System.

(358) According to the requirement of different experiments, MARC-145 cells were either infected with PRRSV at MOIs of 0.1, 1 or 10, or mock infected with phosphate-buffered saline (PBS). After 1 h incubation at 37 C., unbounded viruses were removed by washing thrice with PBS and cultured in DMEM supplemented with 8% FBS at 37 C. for various lengths of time. For the autophagy induction and inhibition experiments, MARC-145 cells were pretreated with varying concentrations of rapamycin or 3-MA for 4 h before viral infection. MARC-145 cells were then infected with PRRSV at MOI of 1. After 1 h incubation at 37 C., unbounded viruses were removed by washing thrice with PBS and cultured in DMEM supplemented with 2% FBS containing varying concentrations of compound, 3-MA or the corresponding amount of dimethyl sulfoxide (DMSO, control) at 37 C. for 24 h. Determinations for each compound dose were in quadruplicate. The CC.sub.50 values were calculated from dose-response curves using the mean values of each set of determinations.

(359) Results

(360) Anti-Enzymatic Activity

(361) The anti-enzymatic activity of representative compounds against the DDX3 helicase is reported in Table 5.

(362) TABLE-US-00006 TABLE 5 Activity of representative compounds of the invention against DDX3 Helicase. Compound ID Structure ID.sub.50 (M).sup.a EI01D published reference compound.sup.6 embedded image 1 8a nd 20a 0.3 8b 3.36 8c 22.8 8f n.a 8g 0.98 20b 0.5 20e 0.94 20f 0 1 22a 0.3 22b 0.17 20d n.a 22g n.a 35a 17.5 35b 20 35e n.a 35h 40 35i 2.9 36 0 0.9 37 1.3 38 0.4 39 5.1 42c 0.3 20c 6 81 1 49 4.9 50 14 51 0.8 52 0 2.49 55a 0.12 55b 0.2 55e 0.9 55f 0.5 55g embedded image 10 15a 1.47 15b 2.0 58a 0.37 64a n.a 64b 0 52.2 64d 0.4 66d 0.4 67d n.a 64e 0.16 68e n.d* 65a 15.5 65c n.a 134 1 112 1 106 00 0.1 8e 01 0.6 80 02 0.4 86 03 1 55h 04 0.1 .sup.aIC.sub.50: inhibiting concentration 50 or needed dose to inhibit 50% of the enzyme, n.a. Compound not active. *not determined

(363) Several DDX3 inhibitors of the invention showed submicromolar activity. In particular compounds 22b, 55a, 55b, 64e are approximately ten-fold more active than compound EI01D previously reported.

(364) TABLE-US-00007 TABLE 6 Selectivity data on compound 20a ATPase DDX3 DDX1 NS3 (DENV) NS3 (HCV) IC.sub.50, M IC.sub.50, M IC.sub.50, M IC.sub.50, M >200 >200 >200 16.8 [a]The value >200 indicates that less than 20% of inhibition was observed at 200 M, the highest concentration tested.

Example 26

(365) Antiviral Activity

(366) Selected compounds from Table 5 were tested against the viruses in which DDX3 is involved.

(367) The antiviral potencies and toxicity of the most active compounds are summarized in the Tables 7-15 below. It is important to note that DDX3 inhibitors identified are able to inhibit the replication of different viruses such as HCV, HIV, DENV, WNV, JEV.

(368) TABLE-US-00008 TABLE 7 Antiviral and cytotoxic activity of selected compounds against Hepatitis C Virus (HCV) replicon system. Compound ID EC.sub.50 (M).sup.a CC.sub.50 (M).sup.b EI01D.sup.* >86 86 20a 0.97 49.77 8b 5.73 100 8f >36 36 8g 36 295 20b 0.8 189 20e 8.55 51.8 20f 28.8 44.4 22a 0.3 200 22b 0.67 46.8 35b 28.9 >370 35e >125 >125 35f >125 >125 35h 43.5 128 35l 19.3 201.7 36 75 >150 37 11.7 179.7 38 0.5 23.2 39 4.3 28.6 41c 0.8 8.6 20c >125 >125 81 1.99 74.16 49 7.16 11.24 50 22.8 244.9 51 0.6 6.7 55r 7.3 50.7 55a 0.4 >340 55b 0.2 183 21b 6.11 42.05 55e 1 245 55f 0.9 >312 55g 12.4 >278 15b 3.65 180 58a 204 215 66d >58.6 58.6 64e 59.1 201 8d 0.67 290 .sup.aEC.sub.50: Effective concentration 50 or needed concentration to inhibit 50% HCV-induced cell death, evaluated with the luciferase method in LucUbiNeo-ET cells .sup.bCC.sub.50 Cytotoxic concentration 50 or needed concentration to induce 50% death of non-infected cells, evaluated with the MMT method in LUNET cells. *Compound previously published .sup.6

(369) Data showed that compound EI01D previously reported was found completely inactive against HCV.

(370) TABLE-US-00009 TABLE 8 Antiviral and cytotoxic activity of selected compounds against Hepatitis C Virus (HCV) infectious cell culture system. HCV Cmpd ID EC.sub.50 .sup.a CC.sub.50.sup.b 20a 3.8 10.1 22a 0.6 94.4 20b 30.0 209 .sup.a EC.sub.50: Effective concentration 50 or needed concentration to inhibit 50% HCV Jcl (genotype 2a virus)-induced cell death, evaluated with the immunohistochemistry (IHC) method against the HCV NS5A antigen in HuH7.5 cells. .sup.bCC.sub.50: Cytotoxic concentration 50 or needed concentration to induce 50% death of non-infected cells, evaluated with the MTT method in HuH7.5 cells.

(371) TABLE-US-00010 TABLE 9 Antiviral and cytotoxic activity of selected compounds against Immunodeficiency Virus (HIV). CC.sub.50.sup.b EC.sub.50.sup.a PBMC HIV (PBMC) SI 24 h 48 h 72 h 72 h (HIV/PBMC) EIO1D* 100 10 10 49 >1000 >1000 >1000 9.5 >100 64d 2131 332 197.5 31 6.3 64e 219 86.96 63 9.5 6.6 66d 450 356.8 703 26 27 20a >1000 >1000 >1000 30 >33 .sup.aEC.sub.50: Effective concentration 50 or needed concentration to inhibit 50% HIV-induced cell death, evaluated with PBMC cells after 72 h. PBMC: Peripheral Blood Mononuclear Cells .sup.bCC.sub.50 Concentration required to inhibit 50% of cells viability, .sup.c.not determined; *Compound previously published. .sup.6

(372) TABLE-US-00011 TABLE 10 Evaluation of the in vitro antiviral activity (EC.sub.50) and cytotoxicity (CC.sub.50) in the West Nile Virus (WNV) infectious cell culture system. Compound WNV ID EC.sub.50.sup.a CC.sub.50.sup.b 20a 16.05 >500 58a 7.16 60.9 20b 2.83 62.3 22a 0.18 145 .sup.aEC.sub.50: Effective concentration 50 or needed concentration to inhibit 50% WNV-induced cell death, evaluated with Huh7 cells. .sup.bCC.sub.50 Concentration required to inhibit 50% of cells viability.

(373) TABLE-US-00012 TABLE 11 Evaluation of the in vitro antiviral activity (EC.sub.50) and cytotoxicity (CC.sub.50) in the Dengue Virus (DENV) infectious cell culture system. Compound DENV ID EC.sub.50.sup.a CC.sub.50.sup.b 20a 2.55 >787 58a 1.1 99.4 20b 0.13 40.4 22a 0.12 178 .sup.aEC.sub.50: Effective concentration 50 or needed concentration to inhibit 50% DV-induced cell death, evaluated with Huh7 cells. .sup.bCC.sub.50 Concentration required to inhibit 50% of cells viability.

(374) TABLE-US-00013 TABLE 12 Evaluation of the in vitro antiviral activity (EC.sub.50) and cytotoxicity (CC.sub.50) in the JEV infectious cell culture system. Compound JEV ID EC.sub.50 .sup.a CC.sub.50.sup.b EIO1D* 10 >50 20a 20 >50 58a 10 >50 49 7.1 >50 20e 25 >50 64d 6.7 >50 66d 6.1 >50 68e 4.4 >50 36 21.1 >50 55e 3.3 >50 55f 32.8 >50 .sup.a The viral titre was determined by plaque formation assay in baby hamster kidney (BHK-21) cells .sup.bCC.sub.50 Concentration required to inhibit 50% of cells viability. *Published reference compound.sup.6

(375) TABLE-US-00014 TABLE 13 Evaluation of the in vitro antiviral activity (EC.sub.50) in the PRRSV infectious cell culture system. Compound PRRSV ID EC.sub.50 .sup.a 64d 30 .sup.a The viral titre was determined by plaque formation assay in MARC-145 cells

Example 27

(376) Evaluation of Antiviral Activity on HIV-1 Strains Carrying Mutations Conferring Resistance to Drugs Currently Used to Treat HIV Infection.

(377) MT-2 and TZM-bl cell lines and the infectious clones used to evaluate the antiviral activity of compound 16d were all obtained through the AIDS Reagent Program (ARP, Division of AIDS, NIAID, NIH). Drugs susceptibility of NIH clones has been previously characterized through the Phenosense phenotypic assay (available at Quest Diagnostics, Monogram Biosciences laboratory, San Francisco, USA). The features of the reference and resistant viruses are showed in the following table:

(378) TABLE-US-00015 VIRUS (ARP DRUG DEGREE OF CATALOGUE RESISTANCE RESISTANCE TO NUMBER) CLASS MUTATIONS MOST COMMON DRUGS 114 Wild type None Full susceptibility virus to all drugs 11808 PIs Major: V32I, I54V, High level resistance to I84V, L90M atazanavir and lopinavir; Minor: L10F, V11I, intermediate resistance to K20T, L33F, E35G, darunavir A71I, G73S, L89V 7406 NRTIs M41L, L74V, M184V, High level resistance to L210W, T215Y lamivudine, emtricitabine, zidovudine, abacavir; intermediate resistance to tenofovir NNRTIs A98G, G190C High level resistance to efavirenz and nevirapine; low level resistance to etravirine and rilpivirine 7404 NRTIs A62V, V75I, F77L, High level resistance to F116Y, Q151M abacavir and zidovudine; intermediate resistance to lamivudine, emtricitabine and tenofovir 12227 NRTIs M41L, T215Y High level resistance to zidovudine; intermediate resistance to abacavir and tenofovir; low level to lamivudine and emtricitabine NNRTIs K101P, K103N High level resistance to efavirenz, nevirapine and rilpivirine; intermediate resistance to etravirine 12235 NRTIs M41L, D67N, T69D, High level resistance to L74I, L210W, T215Y zidovudine, tenofovir and abacavir; intermediate resistance to lamivudine and emtricitabine NNRTIs A98G, K101E, High level resistance to Y181C, G190A efavirenz, nevirapine, rilpivirine and etravirine 11845 INIs G140S, Q148H High level resistance to raltegravir and elvitegravir; intermediate resistance to dolutegravir PIs: protease inhibitors; NRTIs: nucleoside reverse transcriptase inhibitors; NNRTIs: non-nucleoside reverse transcriptase inhibitors; INIs: integrase inhibitors.

(379) The IC50 values of the HIV-1 wild-type reference strain NL4-3 and viruses carrying resistant mutations were determined in a phenotypic assay consisting in a first cycle of replication in the MT-2 cell line followed by an additional round of replication in TZM-bl cells. MT-2 cells were seeded at a concentration of 50,000 cells/well in a 96-well plate and infected with the reference strain NL4-3 in presence of five-fold dilutions of the compounds. After 48-72 hours, 50 l of supernatant from each well, containing the virus produced in the first round of infection, were used to infect TZM-bl cells seeded in a 96-plate well at a concentration of 30,000 cells/well. Two days later, cells were lysed adding 40 l of Glo Lysis Buffer (Promega) to each well for 5 minutes, than 40 microliters of Bright-Glo Luciferase Reagent (Promega) were added to each well for relative luminescence units (RLU) counting using Glo-Max Multi Detection System (Promega). RLU values from each well were elaborated using the GraphPad v5.0 software to calculate the IC50 of each compound.

(380) TABLE-US-00016 TABLE 14 Evaluation of the in vitro antiviral activity (EC.sub.50) in the HIV infectious cell culture system. Compound HIV ID EC.sub.50 .sup.a 20a 1.1 55b 1.8 55o 21.2 55h 16.2 86 3.0 80 7.35 49 5.2 51 5.5 106 2.2 112 5.5 102 72.8 64d 12.7 134 3.1 64e 1.0 58a 20.2 .sup.a EC.sub.50: Effective concentration 50 or needed concentration to inhibit 50% HIV-induced cell death, evaluated in a phenotypic assay consisting in a first cycle of replication in the MT-2 cell line followed by an additional round of replication in TZM-bl cells.

(381) TABLE-US-00017 TABLE 15 Antiviral activity of compound 20a against HIV-1 strains carrying the most common patterns of resistance mutations selected by drugs currently used to treat HIV-1 infection. Drug resistance IC50 Fold HIV-1 strain[a] class[b] [95% CI] (M) change[c] 114[d] wild type 1.11[0.31-3.90] / 11808 PIs 0.23[0.08-0.65] 0.2 7406 NRTIs 0.33[0.13-0.87] 0.3 7404 NRTIs 0.22[0.11-0.47] 0.2 12227 NNRTIs 0.94[0.21-1.34] 0.8 12235 NNRTIs 0.36[0.15-0.87] 0.3 11845 INIs 0.37[0.26-0.52] 0.3 [a]NIH AIDS Reagent Program catalogue number (www.aidsreagent.org). [b]PIs: protease inhibitors; NRTIs: nucleos(t)ide reverse transcriptase inhibitors; NNRTIs: non nucleos(t)ide reverse transcriptase inhibitors; INIs: integrase inhibitors. [c]Resistant strain IC.sub.50 to wild type strain IC.sub.50 ratio. [d]NL4-3 HIV-1 wild type reference strain.

Example 28

(382) Evaluation of the In Vitro Antiviral Activity in the EBOV Infectious Cell Culture System.

(383) Vero E6 cells were seeded in 48 well plates the day prior infection. 24 hrs after, the cells were infected with EBOV expressing GFP (EBOV/GFP) at an multiplicity of infection (MOI) of 0.1 in the presence of different compounds at 5 M concentration in serum free medium for 1 hr at 37, then inoculum was removed and replace by 3% FCS culture medium containing 5 M drug, cells were then incubated 48 hrs at 37 C. Forty-eight hours afterwards, cells were detached from the plate with trypsin and fixed for 20 min with 3% PBS buffered paraformaldehyde prior to flow cytometry analysis on a Beckman Coulter Gallios apparatus (Beckman, Brea, Calif., USA). The virus input is adjusted to get 50-70% of infected cells at 48 hrs. Infected cells are identified by the expression of GFP (Ebola GFP), as GFP is inserted as a viral gene in ebola genome, GFP intensity (MFI) is related to viral replication. Neg value indicate the background level in the non infected condition. All data represents averages and SD of three independent experiments.

(384) TABLE-US-00018 TABLE 16 Evaluation of the in vitro antiviral activity in the EBOV infectious cell culture system. Compound Normalized % ID infected cells.sup.a 51 60 66d 80 .sup.aThe viral titre was determined in Vero E6 cells

(385) The results demonstrate that compounds showed anti-HIV activity in cells as well as a good inhibitory activity against group IV viruses such as anti-HCV, WNV, JEV and DENY infections. Compounds 20a, 20b, 22a, 22b, 55a and 55b showed the best activity against HCV. Results showed also that drug 20a, 22a and 20b can significantly inhibit DENV and WNV infections. Compounds 51 and 66d are able to affect EBOV replication (Group V virus), demonstrating the activity against ()ssRNA viruses.

(386) In conclusion, the anti-HIV activity of the compounds of the invention was evaluated by in vitro activity using a recombinant human DDX3 protein produced in E. Coli. The antiviral activity of compound 20a was also evaluated with viruses carrying resistance mutations conferring high level resistance to most of the antivirals approved to treat HIV infection. Compound 20a retained full activity against all the resistant viruses tested, confirming its novel mechanism of action and the potential to overcome HIV resistance.

(387) The IC.sub.50 was calculated for each molecule, and represents the concentration of the inhibitor able to reduce the DDX3 helicase activity by 50%. Enzymatic assays showed that compounds are selective inhibitors of the human helicase DDX3. The most active compounds were further optimized and tested in viral diseases.

(388) The results obtained and reported in the Examples show that the compounds of the invention were able to: .sup.1) Inhibit helicase activity of human DDX3 protein by interacting with the RNA binding site and interfering with the subsequent catalytic steps; .sup.2) Suppress HIV-1 replication in infected cells without any toxicity to uninfected cells used as control; .sup.3) Suppress HCV replication in infected cells without any toxicity to uninfected cells used as control; .sup.4) Suppress WNV replication in infected cells without any toxicity to uninfected cells used as control; .sup.5) Suppress DENV replication in infected cells without any toxicity to uninfected cells used as control; .sup.6) Suppress JEV replication in infected cells without any toxicity to uninfected cells used as control; .sup.7) Suppress PRRSV replication in infected cells without any toxicity to uninfected cells used as control; .sup.8) Suppress HIV-1 mutant strains replication in infected cells. .sup.9) Suppress EBOV replication in infected cells without any toxicity to uninfected cells used as control;

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Human helicase DDX3 inhibitors as therapeutic agents

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