Catechol O Methyltransferase Activity Inhibiting Compounds

CATECHOL O-METHYLTRANSFERASE ACTIVITY INHIBITING COMPOUNDS FIELD OF THE INVENTION The present invention relates to pharmacologically active 2-substituted 4,5-dihydroxyisophthalonitriles, or pharmaceutically acceptable salts and esters thereof, as well as to pharmaceutical compositions containing them and to their use as inhibitors of the catechol O-methyltransferase (COMT) enzyme. BACKGROUND OF THE INVENTION Dopamine is deficient in the brain of patients suffering from Parkinson's disease. Levodopa is used orally in the treatment of Parkinson' s disease. Levodopa is a dopamine precursor, which is converted to dopamine in the brain. However, only a small portion of orally administered levodopa reaches the brain, because levodopa is metabolized in the peripheral system by COMT as well as by dopa decarboxylase (DDC). COMT metabolizes levodopa by converting it to 3-O-methyldopa, which is therapeutically ineffective and detrimental When competing with levodopa. COMT inhibitors have been shown to be effective in clinical use for the treatment of Parkinson's disease as an adjunct to levodopa therapy. It is generally thought that the levodopa concentration in plasma reflects the levodopa levels in the brain! It is thus desirable to achieve a high levodopa concentration in plasma. However, optimal levodopa concentration in plasma is not achieved, for example, with the currently used COMT inhibitor entacapone. COMT inhibitors have also been indicated to be useful in the treatment of, for example, hypertension, heart failure and depression (US 5446194) as well as inhibitors for the prevention of diabetic vascular dysfunctions (WO 98/27973). COMT inhibitors have also been disclosed as being useful for treating or controlling pain (WO 01/68083) as well as for treating restless legs syndrome (RLS), which is also known as Ekbom's syndrome (WO 2006/051 154). RLS is characterized by an irresistible urge to move the legs accompanied by other unpleasant sensations deep within the legs. SUMMARY OF THE INVENTION An object f the present invention is to provide further inhibitors of the catechol O-methyltransferase enzyme that can be used for the treatment of diseases or conditions wherein inhibition of COMT is indicated to be useful. Accordingly, an object of the present invention is to provide further compounds to be used as COMT inhibiting agents in the treatment of mammals, including humans and animals. Furthermore, pharmaceutical compositions containing the present compounds are provided. The COMT inhibitors of the invention provide in levodopa therapy an improved levodopa concentration in plasma. DETAILED DESCRIPTION OF THE INVENTION The invention includes within its s i pe all the possible geometric isomers, e.g. Z and E isomers (cis and trans isomers), of the compounds as well as all the possible optical isomers, e.g. diastereomers and ehantiomers, of the compounds. Furthermore, the invention includes in its scope both the individual isomers and any mixtures thereof, e.g. racemic mixtures. The individual isomers may be obtained using the corresponding isomeric forms of the starting material or they may be separated after the preparation of the end compound according to conventional separation methods. For the separation of optical isomers, e.g. enantiomers, from the mixture thereof conventional resolution methods, e.g. fractional crystallization, may be used The invention includes within its scope all the possible tautomers, or equilibrium mixtures thereof, of the compounds. In tautomers a hydrogen migrates from one atom of the compound to another atom of the compound. Representative examples of tautomers include, but are not limited to, keto/enol and nitroso/oxime. The compounds of formula can be prepared by a variety of synthetic routes analogously to r according to methods known in the literature using suitable starting materials. While many general methods are available for the generation of a cyano group, most of them are not directly usable in the field of catechol chemistry. For instance, the Sandmeyer reaction provides an extremely reactive catecholic amine as an intermediate which creates serious preparative challenges. Some methods useful for the preparation of the compounds of formula I are described below. The dicyano grouping can be constructed efficiently using simple starting materials essentially via two ways, either synthesizing two formyl groups simultaneously or building the second formyl group on a benzaldehyde derivative. In both cases the formyl groups are subsequently transformed into cyano groups in good yield. Further transformations provide a useful intermediate from which numerous final products can be formed. NMR (400 MHz, methanol-^) pp 7.54-7.58 (m, 1 H) 7.30 (s, 1 H) 7.23-7.29 (m, 2 H) 7.06-7.10 (m, 1H) 6.75 (t, 1H) 3.64 (d, 2 H) Example 184: 4,5-Dihydroxy-2-(morpholinomethyl)isophthaIonitrile 2-(Bromomethyl)-4-hydroxy-5-methoxyisophthalonitrile 4-Hydroxy-5-methoxy-2-methylisophthalonitrile ( 1.32 g), NBS (2.48 g), and AE N (164 mg) in DCM (50 ml) were refluxed for 6 h 30 mm. The reaction was allowed to cool overnight to room temperature. The mixture was cooled in an ice bath and insoluble material was filtered off. The filtrate was evaporated to dryness. EtOAc (10 ml) and heptane (10 ml) were added to the residue and the mixture was heated to reflux. Insoluble oil was removed from the hot solvent. The mixture was allowed to cool to room temperature and the precipitate was filtered off. The filtrate was evaporated to dryness. The crude product was chromatographed o er silica gel (EtOAc/heptane/AcOH) . The compound was used without further purification. Yield 646 mg 1H NMR (400 MHz, DMSO-ii6) ppm 1.05 (br s, 1H) 7.74 (s, 1H) 4.73 (s, 2 H) 3.94 (s, 3 4-Hydroxy-5-meth0xy-2-(m0rpholihomethyl)isophthalonitrile Sodium hydride (60% in oil, 116 mg), morpholine (0.25 ml), DMF ( 1 ml) were cooled in an ice bath. 2-(Bromomethyl)-4-hydroxy-5-methoxyisophthalOnitrile (365 mg) was added dropwise in DMF (9 ml). The mixture was stirred for 15 min in an ice bath and 2 h 30 min at room temperature. The reaction was quenched with few drops of water. The mixture was evaporated to dryness. EtOAc (25 ml) was added and insoluble material was filtered off. The filtrate was evaporated to dryness and the resulting residue was chromatographed over silica gel (EtOAc/heptane/AcOH). Yield 148 mg NMR (400 MHz, DMSO- ) ppm 11.79 (br s, 1H) 7.62 (s, 1H) 3.90 (s, 3 H) 3.61 (s, 2 H) 3:51-3.56 (m, 4 H) 2.40-2.46 (m, 4 H) 4,5-Dihydroxy-2-(morpholinomethyl)isophthalonitrile 4-Hydroxy-5-methoxy-2-(morpholinomethyl)isophthalonitrile (140 mg) and acetonitrile (5 ml) were mixed. Boron tribromide (2.05 ml, 1M in DCM) in DCM (15 ml) was added dropwise to the mixture at room temperature. The reaction was stirred for 2 h, and then quenched with water (0.22 ml). The mixture was stirred in an ice bath. The precipitate was filtered and washed with small amount of DCM. Ethanol (4 ml) was added to the solid and the mixture was heated to reflux. Insoluble material was filtered off from the hot solution. The amount of solvent was reduced to about 1.5 ml and the mixture was heated to reflux followed by cooling to room temperature. Ethanol was slowly evaporated by stream of air until precipitate formed. The mixture was stirred in an ice bath, filtered and was ed with few drops of ethanol. Yield 45 mg l NMR (400 MHz, DMSO--4) ppm 9.98 (br s, 2 H) 7.07 (s, 1H) 4.43 (s, 2 H) 3.69-3.98 (m, 4 H) 3.39 (br s, 4 H) '' . · , . . , . Example 185: 2-((Diethyiamino)metKyl)-4,5-dihydroxyisophthalonitriIe hydrochloride 2-((Diethylamino)methyl)-4-hydroxy-5-methoxyisophthalonitrile hydrochloride 4-Hydroxy-5-methoxy-2-methylisophthalonitrile (188 mg), NBS (354 mg), and AIBN (41 mg) in EtOAc (10 ml) were refluxed for 2 h. The reaction was cooled in an ice bath and diethylamine (0.52 ml) in methanol (10 ml) was added. The mixture was stirred overnight at room temperature and evaporated to dryness. The residue was mixed with toluene and evaporated to dryness. The resulting material was dissolved in EtOAc and cooled in an ice bath: HCl in EtOAc was added dropwise. The precipitate was filtered and washed with cold EtOAc. The crude product was recrystallized from EtOAc/ethanol. Yield 180 mg NMR (400 MHz, DMSO- ) ppm 8.69 (br s, 1 H) 7.81 (s, 1H) 4.39 (s, 2 H) 3.96 (s, 3 H) 3.21 (q, 4 H) 1.33 (t, 6 H) 2-((Diethylamino)methyl)-4,5-dihydroxyisophthalonitrile hydrochloride 2-((Diethylamino)methyl)-4-hydroxy-5-methoxyisophthalonitrile hydrochloride (170 mg) and acetonitrile (20 ml) were cooled to -20 °C. Boron tribromide (1.7 ml, 1M in DCM) was added dropwise to the mixture. The reaction was allowed to warm overnight to room temperature and then cooled in an ice bath. Methanol was added (10 ml) followed by heating to reflux for 1 h. The mixture was evaporated to dryness. 1M HCl in diethyl ether was added dropwise. The precipitate was filtered. The solid was triturated with EtOAc/ethanol, toluene/EtOAc/AcOH and EtOAc. The crude product was chromatographed over silica gel (DCM/methanol). The product was dissolved in EtOAc and cooled in an ice bath. 1M HCl in EtOAc was added dropwise. The precipitate was filtered and washed with cold EtOAc. Yield 20 mg 1H NMR (400 MHz, DMSO-4) ppm 8.37 (br s, 3 H) 7.41 (s, 1H) 4.36 (br s, 2 H) 3.20 (br s, 4 H) 1.31 (t, 6 H) Example 186: 4,5-Dihydroxy-2-(((2-hydroxyethyl)amino)methyl)isophthalonitrile hydrochloride (1:1) 4-Hydroxy-2-(((2-hydroxyethyl)aitiino)methyl)-5-methoxyisophthalohitrile 4-Hydroxy-5-methoxy-2-methylisophthaloriitrile (188 mg), NBS (356 mg), and A 3N (4 1 mg) in EtOAc (10 ml) were refluxed for 2 h. The reaction was cooled in an ice bath. Ethanolamirie (0.18 ml) was dissolved in methanol (10 ml) and added to the mixture. The reaction mixture was stirred for 2 h at room temperature and evaporated to dryness. The residue was triturated with EtOAc and methanol. Yield 47 mg 1H NMR (400 MHz, DMSO- ) ppm 8.68 (br s, 1H) 7.14 (s, 1H) 5.04 (br s, 1H) 4.63 (s, 2 H) 3.63 (s, 3 H) 3.57-3.65 (m, 4 H) 4,5-Dihydroxy-2-(((2-hydroxyethyl)amino)methyl)isophthalonitrile hydrochloride (1:1) 4-Hydroxy-2-(((2-hydroxyethyl)amino)methyl)-5-methoxyisophthalonitrile (47 mg), aluminum chloride (76 mg) and sodium iodide (57 mg) in acetonitrile were refluxed for 2 h. The reaction was cooled and quenched with 2 N HCl (1ml). The organic phase was separated and the aqueous phase was washed with acetonitrile. The combined organic phases were evaporated to dryness. The residue was treated with methanol, and then the solvent was decanted. The solution was treated with 1M HCl in EtOAc in an ice bath. The product was filtered. Yield 8 mg 1H NMR (400 MHz, DMSO- ) ppm 11.21 (br s, 1 H) 9.94 (br s, 1 H) 9.29 (br s, 1H) 7.86 (br s, 1 H) 4.95 (br s, 2 H) 3.82 (br s, 2 H) 3.72 (br s, 2 H) Example 187: 4,5-Dihydroxy-2-(3-hydroxypropyl)isophthalonitrile 4-Hydroxy-2-(3-hydroxypropyl)-5-methoxyisophthalaldehyde 5-(3-Hydroxypropyl)-2-methoxyphenol (4.51 g) and hexamethylenetetramine (7.29 g) in AcOH (50 ml) were refluxed for 8 h. Concentrated HCl (9.1 ml) was added and the mixture was refluxed for 2 h. Brine (50 ml) was added and the mixture was extracted thrice with DCM (75 ml). The combined organic phases were dried (Na2S0 4) and evaporated to dryness. The residue was filtered through silica gel cake using toluene/EtOAc/AcOH (8:1:1) solvent mixture. The mixture was evaporated to dryness. The compound was used without further purification. Yield 8.86 g 4-Hydroxy-2-(3-hydroxypropyI)-5-methoxyisophthalonitriIe 4-Hydroxy-2-(3-hydroxypropyl)-5- methoxyisOphthalaldehyde (8.86 g), hydroxylamine hydrochloride (7.75 g) and anhydrous sodium acetate (12.20 g) in formic acid (50 ml) were refluxed for 5 h. The reaction mixture was evaporated to dryness. Acetone (100 ml) was added to the residue and insoluble material was filtered off. The filtrate was evaporated to dryness. THF (100 ml), acetic anhydride (18.99 g) and triethylarriine (51.9 ml) was added. The reaction was stirred at room temperature until reaction stopped (TLC). The mixture was evaporated to dryness. The remainder was cooled in an ice bath. Water (100 ml) was added to the residue and pH wa adjusted to about 1 with concentrated HCl. The aqueous phase was extracted thrice with EtOAc (100 ml) and the combined organic phases were washed with brine (25 ml). The organic phase was extracted twice with 2 N NaOH (75 ml). The combined aqueous phases were cooled in an ice bath and pH was adjusted to about 1 with concentrated HCl. The precipitate was filtered and washed with cold water. Yield 870 g NMR (400 MHz, DMSO-<2 ) ppm 11.78 (br s, 1H) 7.62 (s, 1H) 3.89 (s, 3 H) 3.46 (t, 2 H) 2.81-2.87 (m, 2 H) 1.68-1.77 (m, 2 H) 4,5-Dihydroxy-2-(3-hydroxypropyl)isophthalonitrile To a mixture of 4-hydroxy-2-(3-hydroxypropyl)-5-methoxyisophthalonitrile (570 mg), DCM (50 ml) under nitrogen atmosphere was added 1M boron tribromide solution in DCM (8.1 ml) at room temperature. The reaction mixture was refluxed for 10 h. 5% sodium sulfite was added to the reaction mixture until no color change was seen. The precipitate was filtered off and washed with water. The solid was dissolved in 1M sodium hydrogen carbonate and washed with EtOAc. The aqueous phase was cooled in an ice bath and 6 N HC1 was added. The product was filtered and washed with water. Yield 300 mg NMR (400 MHz, DMSO-d6) ppm 11.06 (br s, 2 H) 7.22 (s, 1H) 4.57 (br s, 1H) 3.45 (t, 7=6.32 Hz, 2 H) 2.71-2.94 (m, 2 H) 1.55-1.80 (m, 2 H) ·' . : · ' ' Example 188: 2-Amino-4,5-dihydroxyisophthaIonitrile 3-(BenzyIamino)-2,4-dicyario-6-methoxyphenyl tert-butyl carbonate Sodium hydride (2.48 g) and benzylamine ( 1 1.29 ml) in toluene (50 ml) were heated at 70 °C for 1 min Under nitrogen atmosphere. The mixture was cooled in an ice bath and Pd2(dba)3 (0.14 g), rac-2,2'-bis(diphenylphosphino)-l,l'-binaphthalene (0.23 g) and 3-bromo-2,4-dicyano-6-methoxyphenyl tert-butyl carbonate (3.65 g) were added. The mixture was heated at 85 °C for 3 h and then cooled in an ice bath. 4 N HC1 was added to the mixture and the mixture was extracted thrice with EtOAc. The combined organic phases were washed thrice with brine, dried (Na2S0 ), filtered and evaporated to dryness. The residue was triturated with hot 75% ethanol and cooled in a ice bath; The product was filtered off and washed with 50% ethanol. Yield 2.96 g 1H NMR (400 MHz, DMSO- ) ppm 7.47 (s, 1H) 7.25-7.35 (m, 4 H) 7.17-7.25 ( , 1H) 6.56 (t, 7=6.90 Hz, 1 H) 4.74 (d, 7=7.03 Hz, 2 H) 3.70 (s, 3 H) 1.32 (s, 9 H) : 2-(Benzylamino)-4-hydroxy-5-methoxyisophthalonitrile 3-(Benzylamino)-2,4-dicyaho-6-methoxyphenyl tert-butyl carbonate and DCM (40 ml) were stirred at room temperature. Phosphoric acid (2.1 g, 85%, aq.) was added arid the reaction mixture stirred at 40 °C until the reaction was completed. The mixture was cobled in an ice bath. The solvent was decanted and the residue was washed with cold DCM. The remainder was triturated with 10% ethanol and cooled in an ice bath. The solids were ' filtered off and washed with ice cold water. Yield 1.03 g NMR (400 MHz, DMSO- ) ppm 11.54 (br s, 1 H) 7.27-7.36 (m, 5 H) 7.19-7.26 (m, 1 H) 6.48 (t, 7=6.90 Hz, 1H) 4.74 (d, 7=6.78 Hz, 2 H) 3.68-3.80 (m, 3 H) 2-Amino-4,5-dihydroxyisophthalonitriIe 2-(Benzylamino)-4-hydroxy-5-methoxyisophthalonitrile (520 mg) was slowly added to a solution of aluminum chloride (993 mg) and sodium iodide ( 1116 mg) in acetonitrile (15 ml) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The mixture was evaporated to dryness. 1N HC1 (21 ml) was added followed by addition of 1M sodium sulfite until o color change was seen. The organic phase was separated. The aqueous phase was extracted thrice with EtOAc. The organic phases were combined, washed with brine, dried (Na2S0 4), filtered and evaporated to dryness. Heptane (9 ml) and EtOAc ( 1 ml) was added and heated to reflux. Trie crude product was filtered from the hot solution and chromato graphed over silica gel. Yield 160 mg ΉNMR (400 MHz, OUSO-d6) ppm 10.98 (br s, 1 H) 9 (br s, 1 H) 6.97 (s, 1 H) 5.85 (s, 2 H) ' ' Example 189: 4,5-Dihydroxy-2-(pyrroIidin-l-yl)isophthaIonitrile tert-Butyl 2,4-dicyano-6-methoxy-3-(pyrroIidin-l -yl)phenyl carbonate Using the procedure analogous to Example 188, 3-bromo-2,4-dicyano-6-methoxyphenyl tert-butyl carbonate (1.06 g) was converted t6 tert-butyl 2,4-dicyano-6-methoxy-3- (pyrrolidin-l-yl)phenyl carbonate. The crude product was triturated with hot ethanol. Yield 1.03 g 1H NMR (400 MHz, DMSO--4) ppm 7.53 (s, 1H) 3.77 (s, 3 H) 3.68-3.73 (m, 4 H) 1.88- 1.96 (m, 4 ) 1.40 (s, 9 H) 4-Hydroxy-5-methoxy-2-(pyrrolidin-l-yl)isophthalonitrile Using the procedure analogous to Example 188, tert-butyl 2,4-dicyano-6-methoxy-3- (pyrrolidin-l-yl)phenyl carbonate (530 mg) was converted to 4-hydroxy-5-methoxy-2- (pyrrolidin-l-yl)isophthalonitrile. Yield 260 mg 1H NMR (400 MHz, DMSO-J 6) ppm 11.48 (br s, 1H) 7.34 (s, 1H) 3.80 (s, 3 H) 3.70 (t, 7=6.40 Hz, 4Ή ) 1.88-1.93 ( , 4 H 4,5-Dihydroxy-2-(pyrrolidin-l-yl)isophthalonitrile Using the procedure analogous to Example 188, 4-hydroxy-5-methoxy-2-(pyrrolidin-lyl) isophthalonitrile was converted to 4,5-dihydroxy-2-(pyrrolidin-l-yl)isophthalonitrile. The crude product was dissolved in 8 N NaOH and washed twice with EtOAc. The aqueous phase was cooled in an ice bath and concentrated HC1 was added. The precipitate was filtered and washed with water. Yield 32 mg 1H NMR (400 MHz, DMSO-d ) ppm 10.61 (br s, 2H) 7.02 (s, 1H) 3.64 (t, 7=6.30 Hz, 4 H) 1.90 (m, 4 H) Example 190: 2-(2,6-DimethyImorphoIino)-4,5-dihydroxyisophthalonitrile tert-BUtyl 2,4-dicyario-3-(2,6-dimethylmorpholino)-6-methoxyphehyl carbonate Using the procedure analogous to Example 188, 3-bromo-2,4-dicyario-6-methoxyphenyl tert-butyl carbonate (706 mg) was converted to tert-butyl 2,4-dicyano-3-(2,6-dimethylmoipholirio)-6 rriethoxyphenyl carbonate. Yield 159 mg 1H NMR (400 MHz, DMSO- ) ppm 7.69 (s, 1H) 3.82 (s, 3 H) 3.67-3.77 ( , 2 H) 3.26 (d, 7=1 1.29 Hz, 2 H) 2.94 (dd, 7=1 1.80, 10.04 Hz, 2 H) 1.40 (s, 9 H) 1.1 1 (d, 7=6.27 Hz, 6 H) 2-(2,6-Dimethylmorpholino)-4-hydroxy-5-methoxyisophthalonitriIe U ing the procedure analogous to Example 188, tert-butyl 2,4-dicyano-3-(2,6-dimethylmorpholino)-6-methoxyphenyl carbonate (159 mg) was converted to 2-(2,6-dimethylmorpholino)-4-hydroxy-5-methoxyisophthalonitrile. To isolate the crude product from the reaction mixture, brine was added. The mixture was extracted thrice with EtOAc. The combined organic phases were dried (Na S0 4), filtered end evaporated to dryness. Yield 139 mg 1H NMR (400 MHz, DMSO-d6) ppm 11.74 (br s, 1H) 7.50 (s, 1H) 3.85 (s, 3 H) 3.66-3.75 (m, 2 H) 3.23 (d, 7=1 54 Hz, 2 H) 2.88-2.96 (m, 2 H) 1.10 (d, 7=6.27 Hz, 6 H) 2-(2,6-Dimethylmorpholino)-4,5-dihydroxyisophthalonitrile Using the procedure analogous to Example 188, 2-(2,6-dimethylmorpholino)-4-hydroxy-5-methoxyisophthalonitrile (139 mg) was converted to 2-(2,6-dimethylmorpholino)-4,5-dihydroxyisophthalonitrile. The crude product was triturated with hot toluene. Yield 5.7 mg 1H NMR (400 MHz, DMSO- ) ppm 11.41 (br s, 1 H) 10.63 (br s, 1 H) 7.14 (s, 1 H) 3.53- 3.80 (m, 2 H) 3.16 (d, J=11.29 Hz, 2 H) 2.89 (d, 7=11.05 Hz, 2 H) 1.09 (d, 7=6.27 Hz, 6 H) Example 191: 4,5-Dihydroxy-2-morpholinoisophthalonitrile tert-Butyl 2,4-dicyano-6-methoxy-3-morpholinophenyl carbonate Using the procedure analogous to Example 188, 3-bromo-2,4-dicyano-6-methoxyphenyl tert-butyl carbonate (706 mg) was converted to tert-butyl 2,4-dicyano-6-methoxy-3-morpholinophenyl carbonate. The crude product was crystallized from ethanol. Yield 312 mg NMR (400 MHz, DMSO- ) ppm 7.70 (s, 1 H) 3.83 (s, 3 H) 3.69-3.77 (m, 4 H) 3.28- 3.34 (m, 4 H) 1.40 (s, 9 H) 4-Hydroxy-5-methoxy-2-morpholindisophthalonitrile Using the procedure analogous to Example 188, tert-butyl 2,4-dicyano-6-methoxy-3-morpholinopheriyi carbonate (312 mg) was converted to 4-hydroxy-5-methoxy-2-morpholinoisophthalonitrile. The crude product was triturated with diethyl ether. Yield 109 mg 1H NMR (400 MHz, DMSO-¾) ppm 11.76 (br s, 1 H) 7.49 (s, 1H) 3.85 (s, 3 H) 3.71 (t, 7=4.02 Hz, 4 H) 3.28 (t, 7=4.52 Hz, 4 H) 4,5-Dihydroxy-2-morpholinoisophthalonitrile Using the procedure analogous to Example 188, 4-hydroxy-5-methoxy- 2-morpholinoisophthalonitrile (109 mg) was converted to 4,5-dihydroxy-2-of holinoisophthalonitrile. The crude product was dissolved in 4 N NaOH (5 ml) and washed twice with EtOAc (5 ml). The aqueous phase was cooled in an ice bath and pH was adjusted to < 3 with concentrated HC1: The precipitate was filtered and washed thrice with cold water. Yield 26 mg NMR (400 MHz, DMSO-(C]-C6)alkoxy(Ci-C )alkyl, heterocyclyl -(C=0)-, (R7)2N- (C=0)- or R -(0=S=0)-, wherein said aryl or heterocyclyl as such or as part of another group is unsubstituted; R7 is, independently at each occurrence, H or (Ci-C )alkyl; R is, independently at each occurrence, (Ci-C6)alkyl. 5. A compound according to claim 4, wherein Ri is (C]-C )alkyl, (C2-C )alkenyl, aryl, halogen, aryloxy, aryl-S-, (R3)2N-, heterocyclyl, heteroaryl, aryl(C -C6)alkyl or aryl(C2-C )alkenyl, wherein said aryl, heterocyclyl or heteroaryl as such or as part of another group is unsubstituted or substituted with 1, 2 or 3 substituent(s) R6; R3 is, independently at each occurrence, H or (Ci-C6)alkyl; R6 is, independently at each occurrence, (Ci-C )alkyl, halogen, hydroxy, ( - alkoxy, carboxy(C C )alkyl, halo(C C6)alkyl or (R7)2N-(C=0)-; R7 is, independently at each occurrence, H or (Ci-C )alkyl. 6. A compound according to claim 5, wherein Ri is (C2-C6)alkenyl, aryl, halogen, aryloxy, aryl-S-, (R3)2N-, heteroaryl, aryl(C -C6)alkyl or aryl(C2-C6)alkenyl, wherein said aryl or heteroaryl as such or as part of another group is unsubstituted or substituted with 1 or 2 substituent(s) R6; R3 is, independently at each occurrence, H or (C C6)alkyl; R6 is, independently at each occurrence, (C -C )alkyl, halogen, (C1-C )alkoxy, carboxy(C C6)alkyl or halo(C -C )alkyl. 7. A compound according to claim 6, wherein Ri is (C2-C )alkenyl, aryl, halogen, aryl-S-, heteroaryl or aryl(Ci-C )alkyl, wherein said aryl or heteroaryl as such or as part of another group is unsubstituted or substituted with 1 or 2 substituent(s) R6; R is, independently at each occurrence, (CrC )alkyl, halogen or (Ci-C )alkoxy. 8. A compound according to claim 7, wherein Ri is (C2-C )alkenyl, halogen, aryl-S- or ary d -C^alkyl, wherein said aryl as part of another group is unsubstituted or substituted with 1 or 2 substituent(s) R6; R6 is, independently at each occurrence, (Ci-C )alkyl, halogen or (C1-C )alkoxy. 9. A compound according to claim 7, wherein is (C2-C6)alkenyl, aryl, aryl-S-, heteroaryl or aryl(Ci-C )alkyl, wherein said aryl or heteroaryl as such or as part of another group is substituted with 1 or 2 substituent(s) R6; · ; R is, independently at each occurrence, (C -C6)alkyl or (CrC ^alkoxy. 10. A compound according to claim 9, wherein Ri is (C2-C6 )alkenyl, aryl-S- or aryl(C]-C6)alkyl, wherein said aryl as part of another group is substituted with 1 or 2 substituent(s) R ; R6 is, independently at each occurrence, (Ci-C )alkyl or (Ci-C 6)alkoxy. 11. A compound according to claim 7, wherein Ri is (C2-C6 )alkenyl. 12. A compound according to claim 7, wherein Ri is aryl, wherein said aryl is unsubstituted or substituted with 1 or 2 substituent(s) R6; R6 is, independently at each occurrence, (C1-C )alkyl, halogen or (Ci-C )alkoxy. 13. A compound according to claim 7, wherein Ri is aryl-S-, wherein said aryl is unsubstituted or substituted with 1 or 2 substituent(s) R6; R6 is, independently at each occurrence, (CrC 6)alkyl, halogen or (Q-Ceialkoxy. 14. A compound according to claim 7, wherein is heteroaryl, wherein said heteroaryl is unsubstituted or substituted with 1 or 2 substituent(s) R ; R is, independently at each occurrence, (C -C )alkyl, halogen or (C -C6)alkoxy. 15. A compound according to claim 7, wherein R is aryl(Ci-C 6)alkyl, wherein said aryl is substituted with 1 or 2 substituent(s) 6', R is, independently at each occurrence, ( - alkyl or (Ci-C )alkoxy. 16. A compound according to claim 1, wherein the compound is 2-bromo-4,5-dihydroxyisophthalonitrile, 4,5-dihydroxy-2-(phenylethynyl)isophthalonitrile, 4.5- dihydroxy-2-(prop-l-ynyl)isophthalonitrile, 4,5-dihydroxy-2-(l -methyl- 1Hpyrrol- 2-yl)isophthalonitrile, 4,5-dihydroxy-2-(thiophen-2-yl)isophthalonitrile, 2-(furan-2-yl)-4,5-dihydroxyisophthalonitrile, 3',4',5'-trifluoro-3,4-dihydroxybiphenyl-2,6-dicarbonitrile, 4,5-dihydroxy-2-(naphthalen- 1-yl)isophthalonitrile, 4'-tert-butyl-3,4-dihydroxybiphenyl-2,6-dicarbonitrile, 3,4-dihydroxy-4'-(hydroxymethyl)biphenyl-2,6-dicarbonitrile, 4,5-dihydroxy-2- (naphthalen-2-yl)isophthalonitrile, 3,4-dihydroxy-4'-(isopropylthio)biphenyl- 2.6- dicarbonitrile, 3,4-dihydroxy-4'-(methylthid)biphenyl-2,6-dicarbonitrile, 3,4-dihydroxy-4'-isopropoxybiphenyl-2,6-dicarbonitrile, 4'-(ethylthio)-3,4-dihydroxybiphenyl-2,6-dicarbonitrile, 3,4-dihydroxy-4' -isopropoxy-3 ' ,5 ' -dimethylbiphenyl-2,6-dicarbonitrile, 4'-butyl-3,4-dihydroxybiphenyl-2,6-dicarbonitrile, 3,4-dihydfoxy-2' ,4' ,5' -trimethylbiphenyl-2,6-dicarbonitrile, 3,4-dihydroxy-2',5'-dimethylbiphenyl-2,6-dicarbonitrile, 2-cyclohexenyl-4,5-dihydroxyisophthalonitrile, 3'-ethyl-3,4-dihydroxybiphenyl-2,6-dicarbonitrile, 3,4-dihydroxybipheriyl-2,4',6-tricarbonitrile, 3,4-dihydroxy-4'- (isopropylsulfonyl)biphenyl-2,6-dicarbonitrile, 2',6'-dicyano-3',4'-dihydroxy- N,N-dimethylbiphenyl-4-sulfonamide, (E)-4,5-dihydroxy-2-(pent-lenyl) isophthalonitrile, 2',6'-dicyano-3',4'-dihydroxybiphenyl-3-carboxylic acid, 3,4-dihydroxy-4 , -(l-methoxyethyl)biphenyl-2,6-dicarbonitrile, (E)-2-(3,3-dimethylbut-l-enyl)-4,5-dihydroxyisophthalonitrile, 3,4-dihydroxy-2'-methylbiphenyl-2,6-dicarbonitrile, (E)-2-(2-cyclohexylvinyl)-4,5-dihydroxyisophthalonitrile, (Z)-4,5-dihydroxy-2-(prop- -enyl)isophthalonitrile, 3-(2' . '- cyano- ' ,4'-dihydroxybiphenyl-4-yl)propanoic acid, 3,4-dihydroxy- 3 , -(hydroxymethyl)biphenyl-2,6-dicarbonitrile, 3,4-dihydroxy-3'- (methoxymethyl)biphehyl-2,6-dicarbonitrile, 2 ,6 ' -dicyano-3 ' ,4 ' -dihydroxy- N,N-dipropylbiphenyl-4-carboxamide, (E)-4,5-dihydroxy-2-(prop-lenyl) isophthalonitrile, 3,4-dihydroxybiphenyl-2,6-dicarbonitrile, 3' ,4 ' -dichloro- 3,4-dihydroxybiphenyl-2,6-dicarbonitrile, 3,4-dihydroxy-3 ' - (trifluoromethyl)biphenyl-2,6-dicarbonitrile, 2-(furan-3-yl)-4,5-dihydroxyisophthalonitrile, 3,4-dihydroxy-4'-(trifluoromethyl)biphenyl-2,6-dicarbonitrile, 4,5-dihydroxy-2-(thiophen-3-yl)isophthalonitrile, 4,5-dihydroxy- 2-(5-methylfuran-2-yl)isophthalonitrile, 4,5-dihydroxy-2-(5-methylthiophen-2-yl)isophthalonitrile, 2-benzyl-4,5-dihydroxyisophthalonitrile, 2-(benzofuran-2-yl)-4,5-dihydroxyisophthalonitrile, 2-(5-chlorothiophen-2-yl)-4,5-dihydroxyisophthalonitrile, 2-(benzo[b]thiophen-2-yl)-4,5-dihydroxyisophthaloriitrile, (E)-4,5-dihydroxy-2-styrylisophthalonitrile, 4'-ethyl- 3.4-dihydroxybiphenyl-2,6-dicarbonitrile, 3,4-dihydroxy-3 ' ,5' -dimethylbiphehyl-2,6-dicarbonitrile, 4,5-dihydroxy-2- (phenylthio)isdphthalonitrile, 4,5-dihydroxy-2-(p-tolylthio)isophthalonitrile, 4,5-dihydroxy-2-(4-methylbenzyl)isophthalonitrile, 2-(4-fluorobenzyl)-4,5-dihydroxyisophthalonitrile, 4,5-dihydroxy-2-(4-hydroxybenzyl)isophthalonitrile, 4.5-dihydroxy-2-(2-methoxybenzyl)isophthalonitrile, 4,5-dihydroxy-2-(4- (trifluoromethoxy)benzyl)isophthalonitrile, 2-(3-fluoro-4-methoxybenzyl)-4,5-dihydroxyisophthalohitriie, 2-(2-fluorobenzyl)-4,5-dihydroxyisophthaloriitrile, 4,5-dihydroxy-2-(2-methylbenzyl)isophthalonitrile, 2-(2,5-dimethylbenzyl)-4,5-dihydroxyisophthalonitrile, 2-(3-fluoro-5-methylbenzyl)-4,5-dihydroxyisophthalonitrile, 3-(2,6-dicyano-3,4-dihydroxybenzyl)benzoic acid, 2- (4-fluoro-3-methylbenzyl)-4,5-dihydroxyisophthalonitrile, 4,5-dihydroxy-2-(3-methylbenzyl)isophthalonitrile, 2-(5-fluoro-2-methoxybenzyl)-4,5-dihydroxyisophthaloriitrile, 2-(3,5-dimethylbenzyl)-4,5-dihydroxyisophthalonitiile, 4,5-dihydroxy-2-(4-isopropylbenzyl)isophthalonitrile, 2-(4-ethylbenzyl)-4,5-dihydroxyisophthaloriitrile, 4,5-dihydroxy-2-(naphthalen-lylrhethyl) isophthalonitrile, 5-(2,6-dicyano-3,4-dihydroxybenzyl)-2-hydroxybenzoic acid, 2-(2,4-dimethylbenzyl)-4,5-dihydroxyisophthalonitrile, 2- (3,6-dihydro-2H-pyran-4-yl)-4,5-dihydroxyisophthalonitrile, 2-cyclopentenyl- 4,5-dihydroxyisophthalonitrile, (E)-3-(2,6-dicyano-3,4-dihydroxyphenyl)acrylic acid, (E)-4,5-dihydroxy-2-(3-methoxyprop-l-enyl)isophthalonitrile, 4,5-dih ro y- -(5-( o holinomethyl)thiophen-2-yl)isophthalonitrile, 3,4-dihydroxy-4'-(morpholine-4-carbonyl)biphenyl-2,6-dicarbonitrile, 2-(5'-hexyl- 2,2' -bithiophen-5-yl)-4,5-dihydroxyisophthalonitrile, 2-( 1-benzyl- 1H-pyrazol-4-yl)-4,5-dihydroxyisophthalonitrile, 2-(5-hexylthiophen-2-yl)-4,5-dihydroxyisophthalonitrile, (Z)-2-(but-2-enyl)-4,5-dihydroxyisophthalonitrile, 4.5-dihydroxy-2-(3-methylbut-2-enyl)isophthalonitrile, (E)-2-(but-2-enyl)-4,5-dihydroxyisophthalonitrile, 4,5-dihydroxy-2-methylisophthalonitrile, 4,5-dihydroxy-2-(2-methylprop- 1-enyl)isophthalonitrile, 3,4-dihydroxy-3 ' -methylbiphenyl-2,6-dicarbonitrile, 4,5-dihydroxy-2-vinylisophthalonitrile, 4,5-dihydroxy-2-(pfop-l-en-2-yl)isophthalonitrile, 2-(2-ethoxythiazol-5-yl)-4,5-dihydroxyisbphthalonitrile, 2-allyl-4,5-dihydroxyisophthalonitrile, 3' -(tertbutoxymethyl)- 3,4 dihydroxybiphenyl-2,6-dicarb0nitrile, tert-butyl 2' ,6' -dicyano-3',4'-dihydroxybiphbnyl-3-carboxylate, 3,4-dihydroxybiphenyl-2,3',6-tricarbonitrile, ^'^'-dicyano-S'^'-dihydroxy-N.N-dipropylbiphenyl-Scarboxamide, 2',6'-dicyano-N-cyclohexyl-3',4'-dihydroxybiphenyl-4-carboxamide, 2',6'-dicyaho-N-cyclohexyl-3',4'-dihydroxybiphenyl-3-carboxamide, 2',6'-dicyano-N,N-diethyl-3',4'-dihydroxybiphenyl-4-carboxamide, 2',6'-dicyano-N,N-diethyl-3',4'-dihydr0xybiphetiyl-3-carboxamide, 2',6'-dicyano-N-ethyi-3',4'-dihydroxybiphenyl-3-carboxamide, 2' ,6' -dicyano-3 ' ,4' -dihydroxy-N,N-dimethylbiphenyl-3-carboxamide, 4' -fluoro 3.4-dihydroxybiphenyl-2,6-dicarbonitrile, 3',4'-diflu0ro-3,4-dihydroxybiphenyl 2.6-dicarbonitrile, 4' -fluoro-3,3 ' ,4-trihydroxybiphenyl-2,6-dicarbonitrile, (E)- 4.5-dihydrcxy-2-(3-phenylprop-l -enyl)isophthalonitrile, 4'-fluoro-3,4-dihydroxy-3'-methoxybiphenyl-2,6-dicarbohitrile, 5-(2,6-dicyano-3,4-dihydroxyphenyl)thiophene-2-carboxylic acid, 3,4-dihydroxy-4'- (methylsulfonyl)biphenyl-2,6-dicarbonitrile, 3,4-dihydroxy-4'-propoxybiphenyl 2.6-dicarbonitrile, 2',6 ,-dicyano-3',4'-dihydroxybiphenyl-4-carboxylic acid, 4'-chloro-3,4-dihydroxy-3'-methylbiphenyl-2,6-dicarbonitrile, 4,5-dihydroxy-2-(5-phenylthiophen-2-yl)isophthalonitrile, 3,4-dihydroxy-4' -isopropylbiphenyl-2,6-dicarbonitrile, 3,4-dihydroxy-4'-propylbiphenyl-2,6-dicarbonitrile, 4,5-dihydroxy-2-(l-phenylvinyl)isophthalonitrile, 2',6'-dicyano-3',4'-dihydroxybiphenyl-2-carboxylic acid, 4-(2,6-dicyano-3,4-dihydroxybenzyl)benzoic acid, (E)-4,5-dihydroxy-2-(4-methoxystyryl)isophthalonitrile, 3,4-dihydroxy-3',4'-dimethylbiphenyl-2,6-dicarbonitrile, (E)-4,5-dihydroxy-2-(4-methylstyryl)isophthalonitrile, 4,5-dihydroxy-2-(6-hydroxynaphthalen-2-yl)isophthalonitrile, 4'-fluoro-3,4-dihydroxy-3'-methylbiphenyl-2,6-dicarbonitrile, 4,5-dihydroxy-2-(3-methylbut- 2-en-2-yl)isophthalonitrile, 2-(2,5-dimethylthiophen-3-yI)-4,5-dihydroxyisophthalonitrile, 2-(2,3-difluoro-4-methylbenzyl)-4,5-dihydroxyisophthalonitrile, 2-(4-(2,6-dicyano-3,4-dihydroxybenzyl)phenyl)propanoic acid, (E)-2-(3-cyclopentylprop-l-enyl)-4,5-dihydrbxyisophthalbnitrile, 4,5-dihydroxy-2-(l-isobutyl-lH-pyrazol-4-yl)isophthalonitrile, 2-(4-(2,6-dicyano-3,4-dihydroxyphenyl)-lH-pyrazol-l-yl) acetic acid, 4,5-dihydrOxy-2-( 1-methyl- 1H-pyrazol-4-yl)isophthalonitrile, 4,5-dihydroxy-2-(3-mcthoxyprop- 1-ynyl)isophthalonitrile, (E)-4,5-dihydroxy-2-(2- (thiophen-3-yl)vinyl)isophthalonitrile, (E)-2-(2-cycloprbpylvinyl)-4,5-dihydroxyisbphthalonitrile, 2' ,6'-dicyano-3 ' ,4'-dihydroxybiphenyl-4-carboxamide, 3,4-dihydroxy-3' ,4'-dimethoxybiphenyl-2,6-dicarbonitrile, 3,4-dihydroxy-3'-isOpropylbiphenyl-2,6-dicarbonitrile, 2-(2,3-dihydrobenzofuran-5-yl)-4,5-diHydroxyisophthalonitrile, 4,5-dihydroxy-2-(6-methoxynaphthalen-2-yl)isophthalonitrile, 4,5-dihydroxy-2-(4- (hydroxymethyl)benzyl)isophthaloriitrile, 2-(2,6-difluoro-3-methylbenzyl)-4,5-dihydroxyisophthalonitrile, 4,5-dihydroxy-2-(4- (trifluoromethyl)phenylthio)isophthalonitrile, 2-(2,4-dimethylphenylthio)-4,5-dihydroxyisophthalonitrile, methyl 3-(4-(2,6-dicyano-3,4-dihydroxyphenylthio)phenyl)propanoate, 4,5-dihydroxy-2-(ptolyloxy) isophthalonitriie, (E)-2-(2,4-difluorostyryl)-4,5-dihydroxyisophthalonitrile, (E)-4,5-dihydroxy-2-(3- (trifluoromethyl)styryl)isophthalonitrile, (E)-4,5-dihydroxy-2-(4-methylpent- 1-enyl)isophthalonitrile, (E)-2-(3,5-difluorostyryl)-4,5-dihydroxyisophthalonitrile, 2-(4-(2,6-dicyano-3,4-dihydroxybenzyl)phenyl)acetic acid, 2-(4-chlorobenzyl)- 4,5-dihydroxyisophthalonitrile, 3,4-dihydroxy-4'-methylbiphenyl-2,6-dicarbonitrile, 3-(4-(2,6-dicyano-3,4-dihydroxybenzyl)phenyl)propanoic acid, 4,5-dihydroxy-2-(4-(trifluoromethyl)benzyl)isophthalonitrile, (E)-4,5-dihydroxy2-( 4-(trifluoromethyl)styryl)isophthalonitrile, 4,5-dihydroxy-2-(ptolylsulfinyl) isophthalonitrile, 4-(2,6-dicyano-3,4-dihydroxyphenylthio)benzoic acid, 2-(4-ethylphenylthio)-4,5-dihydroxyisophthalonitrile, 2-(4-chlorophenylthio)-4,5-dihydroxyisophihalonitrile, 4,5-dihydroxy-2-(otolylthio) isophthalonitrile, methyl 4-(2,6-dicyano-3,4-dihydroxyphenylthio)benzoate, 2-(2-chlorophenylthio)-4,5-dihydroxyisophthalonitrile, methyl 2-(2,6-dicyano-3,4-dihydroxyphenylthio)benzoate, 2-(4-(2,6-dicyano-3,4-dihydrbxyphenylthio)phenyl)acetic acid, 2-(2,6-dicyano-3,4-dihydroxyphenylthio)benz;oic acid, 3-(4-(2,6-dicyano-3,4-dihydroxypheriylthio)phenyl)propanoic acid, 4,5-dihydroxy-2-(4-methoxypheriylthio)isophthalonitrile, methyl 2-(4-(2,6-dicyano-3,4-dihydroxybenzyl)phenyl) acetate, 4,5-dihydr0xy-2-(3-methoxyphettylthio)isophthalonitrile >methyl 4-(2,6-dicyano-3,4-dihydroxyphenoxy)behzoate, 4,5-dihydroxy-2-(pyridin-4-ylthio)isophthalohitrile, 3-(2,6-dicyano-3,4-dihydroxyphenylthio)benzoic acid, 2-(4-cyanophenylthio)-4,5-dihydroxyisophthalonitri½, 4,5-dihydroxy-2- (naphthalen-2-ylthio)isophthalonitrile, 2-(4-(2,6-dicyano-3,4-dihydroxybenzyl)phenyl)-N,N-diethylacetamide, 2-(4-ethylphenoxy)-4,5-dihydroxyisophthalonitrile, 2-(4-acetylphenoxy)-4,5-dihydroxyisophthalonitrile, 4,5-dihydroxy-2-(l-0xo-2,3-dihydro-lH-inden-5-yloxy)isophthalonitrile, 2- (2',6'-dicyano-3',4'-dihydroxybiphenyl-4-yl)acetic acid, 2-(2,4-dimethylphenoxy)-4,5-dihydr0xyisophthalonitrile, 2-(4-chlorophenoxy)-4,5-dihydroxyisophthalohitrile, 4,5-dihydroxy-2 (4- (trifluoromethyl)phenbxy)isophthalonitrile, 4,5-dihydroxy-2-(lH-inden-3-yl)isophthalonitrile, 4,5-dihydGoxy-2-(mo holinomethyl)isophthalonit Gile, 2- ((diethylamino)methyl)-4,5-dihydroxyisophthalonitrile hydrochloride, 4,5-dihydroxy-2-(((2-hydroxyethyl)amino)methyl)isophthalonitrile hydrochloride (1:1), 4,5-dihydroxy-2-(3-hydroxypropyl)isophthalonitrile, 2-amino-4,5-dihydroxyisophthalonitrile, 4,5-dihydroxy-2-(pyrrolidin- -yl)isophthalonitrile, 2- (2,6-dimethylmo holino)-4,5-dihydroxyisophthalonitrile, 4,5-dihydroxy-2-morpholinoisophthalonitrile, 4,5-dihydroxy-2-(isopropylamino)isophthalonitrile, 4,5-dihydroxy-2-(3-methoxypropylamino)isophthalonitrile, 2,4,5-trihydroxyisophthalonitrile, 2-ethyl-4,5-dihydroxyisophthalonitrile, 3,4-dihydroxy-4'-methoxybiphenyl-2,6-dicarbonitrile, 3,4-dihydroxy-3'- (morpholine-4-carbonyl)biphenyl-2,6-dicarbonitrile, N-butyl-2' ,6' -dicyano- 3\4'-dihydroxybiphenyl-4-carboxamide, 2-(3,3-dimethylbutyl)-4,5-dihydroxyisophthalonitrile, 4,5-dihydroxy-2-(piperidin- 1-yl)isophthalonitrile, 2- (hexylamino)-4,5-dihydroxyisophthalonitrile, 2-(cyclohexylamino)-4,5-dihydroxyisophthalonitrile, 4,5-dihydroxy-2-(2-methoxyethylamino)isophthalonitrile, 2-(4-benzylpiperidin- -yl)-4,5-dihydroxyisophthalonitrile, 4,5-dihydroxy-2-(pentan-3-ylamino)isophthalonitrile, (E)-2-(4-ethylbenzylideneamino)-4,5-dihydroxyisophthalonitrile, (E)-4,5-dihydroxy-2-(4-methoxybenzyiideneamin0)isophthalonitrile, (E)-2-(4-fluorobenzylideneamino)- 4,5-dihydr0xyisophthalonitrile, 4,5-dihydroxy-2-tosylisophthalonitrile, 4-(2,6-dicyano-3,4-dihydroxyphenoxy)benzoic acid, 2-(benzo[d]thiazol-2-ylthio)-4,5-dihydroxyisophthalonitrile, 2-(4-fluorophenyltHio)-4,5-dihydroxyisophthalonitrile, 2-(biphenyl-4-ylmethyl)-4,5-dihydroxyisophthaionitrile, 2-(4-chloro-2-methylbenzyl)-4,5-dihydr0xyisophthalonitrile, 2-(2-ethylbenzyl)-4,5-dihydroxyisophthalonitrile, 2- (2,3-dihydro-lH-inden-5-yloxy)-4,5-dihydroxyisophthalonitrile, enantiomer A of 4,5-dihydrdxy-2-(p-tolylsulfinyl)isophthalonitrile, enantiomer B of 4,5-dihydroxy-2-(p-tolylsulfinyl)isophthalonitrile, 2-((cyclohexylmethyl)amino)-4,5-dihydroxyisophthalonitrile, 4,5-dihydroxy-2-(4-phenoxyphenylthio)isophthalonitrile, 4,5-dihydroxy-2-(pyridin-3-yl)isophthalonitrile, 4,5-dihydroxy-2-(4-(2,2,2-trifluoroethyl)benzyl)isophthalonitrile, 4,5-dihydroxy-2-(4-methyl-2- (trifluoromethyI)benzyl)isophthalonitrile, 4,5-dihydroxy-2-((4-(morpholine-4-carbonyl)phenyl)thio)isopththalonitrile, 4,5-dihydroxy-2-(methyl(ptolyl) amino)isophthalonitrile or 4,5-dihydroxy-2-((6-methoxynaphthalen-2-yl)methyl)isophthalonitrile. 17. A compound according to any one of claims 1 to 16 for use as a medicament. 18. A compound according to any one of claims 1 to 16 for use in the treatment of a disease or condition where a COMT inhibiting agent is indicated to be useful. 19. A compound according to claim 18, wherein the disease is Parkinson's disease. 20. Use of a compound according to any one of claims 1 to 16 for the manufacture of a medicament for the treatment of a disease or condition where a COMT inhibiting agent is indicated to be useful. 21. Use according to claim 20, wherein the disease is Parkinson's disease. 22. A method for the treatment of a disease or condition where a COMT inhibiting agent is indicated to be useful comprising administering to a mammal in need of such treatment an effective amount of at least one compound according to any one of claims 1 to 16. 23. A method according to claim 22, wherein the disease is Parkinson's disease. 24. A method according to claim 23, wherein levodopa therapy is potentiated. 25. A pharmaceutical composition comprising as active ingredient at least one compound according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier, diluent, excipient or a mixture thereof. 26. A pharmaceutical composition according to claim 25, wherein the composition further comprises at least one other active ingredient. 27. A pharmaceutical composition according to claim 26, wherein the composition comprises levodopa and carbidopa.