NEW SUBSTITUTED BIPHENYL ANALOGUES AS DUAL INHIBITORS OF AROMATASE AND SULFATASE

Abstract

The present invention relates to new biphenyl derivatives of formula

##STR00001##

These compounds acting as aromatase and sulfatase inhibitors, they are particularly useful for treating pathological conditions or diseases in which aromatase and sulfatase are involved. Moreover, the present invention provides processes for the preparation of these compounds. The invention also relates to pharmaceutical compositions containing said products and their use for the preparation of a medicament, in particular for the treatment of diseases characterized by aromatase and sulfatase activity such as hormone-dependent cancers.

Claims

1. A compound of the formula (Ia) ##STR00063## wherein A represents an aromatic bicyclic ring of up to 10 ring members, containing at least two nitrogen atoms as ring member, and being optionally substituted by one or more substituents selected from halo, alkyl and haloalkyl; B represents an aromatic monocyclic ring of 6 ring members, containing optionally nitrogen atoms as ring member; C represents an aromatic monocyclic ring of 6 ring members, containing optionally nitrogen atoms as ring member and optionally substituted by an alkyl-sulfonyle, the radical RRNSO2O being in meta or para position; R and R represent, independently, hydrogen or alkyl; L is a linker selected from CH2-, NH, N(alkyl)- and N(cycloalkyl-methyl)-; or any pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, of the formula (I) ##STR00064## wherein A represents an aromatic bicyclic ring of up to 10 ring members, containing at least two nitrogen atoms as ring member, and being optionally substituted by one or more substituents selected from halo; B represents an aromatic monocyclic ring of 6 ring members, containing optionally nitrogen atoms as ring member; C represents an aromatic monocyclic ring of 6 ring members, containing optionally nitrogen atoms as ring member; L is a linker selected from CH2-, NH and N(Me)-; or any pharmaceutically acceptable salt thereof.

3. A compound according to claim 1, wherein L is a linker selected from CH2- and NH; or any pharmaceutically acceptable salt thereof.

4. A compound according to claim 1, wherein A represents an aromatic bicyclic ring of 9 ring members, containing at least two nitrogen atoms as ring member, and being optionally substituted by one or more substituents selected from halo; or any pharmaceutically acceptable salt thereof.

5. A compound according to claim 1, wherein A represents an aromatic bicyclic ring of 9 ring members, containing from two to four nitrogen atoms as ring member, and being optionally substituted by one or more substituents selected from halo, the bicyclic ring being the fusion of a ring of 5 ring members and a ring of 6 ring members; or any pharmaceutically acceptable salt thereof.

6. A compound according to claim 1, wherein A represents an aromatic bicyclic ring of 9 ring members, containing from two to four nitrogen atoms as ring member, and being optionally substituted by one or more substituents selected from halo, the bicyclic ring being the fusion of a ring of 5 ring members and a ring of 6 ring members, the ring of 5 ring members containing at least 2 nitrogen atoms and being linked to the linker L; or any pharmaceutically acceptable salt thereof.

7. A compound according to claim 1, wherein A represents an aromatic bicyclic ring selected from ##STR00065## and being optionally substituted by one or more substituents selected from halo; or any pharmaceutically acceptable salt thereof.

8. A compound according to claim 1, wherein A represents a unsubstituted ring; or any pharmaceutically acceptable salt thereof.

9. A compound according to claim 1, wherein the B ring contains at least one nitrogen atom as ring member; or any pharmaceutically acceptable salt thereof.

10. A compound according to claim 1, wherein the B ring contains from one or two nitrogen atoms as ring member; or any pharmaceutically acceptable salt thereof.

11. A compound according to claim 1, wherein B represents an aromatic monocyclic ring selected from ##STR00066## or any pharmaceutically acceptable salt thereof.

12. A compound according to claim 1, wherein the C ring contains no nitrogen atom as ring member; or any pharmaceutically acceptable salt thereof.

13. A compound according to claim 1, wherein C represents an aromatic monocyclic ring containing one nitrogen atoms as ring member; or any pharmaceutically acceptable salt thereof.

14. A compound according to claim 1, wherein the B and C rings contain no nitrogen atom as ring member; or any pharmaceutically acceptable salt thereof.

15. A compound according to claim 1, wherein at least one of the B and C rings contains at least one nitrogen atom as ring member; or any pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition containing, as active ingredient, at least one compound of the general formula according to claim 1, in association with a pharmaceutically acceptable support.

Description

EXPERIMENTAL PART

Example 1

5-((1H-Benzo[d]imidazol-1-yl)methyl)-2-cyano-[1,1-biphenyl]-4-yl sulfamate

Step A. 2-Bromo-4-(bromomethyl)benzonitrile

[0189] A solution of 2-bromo-4-methylbenzonitrile (29 g, 151 mmol), benzoyl peroxide (2.2 g, 9.2 mmol), and N-bromosuccinimide (NBS) (34 g, 151 mmol) in CCl.sub.4 (500 mL) was stirred at 85 C. for 4 hours. The reaction mixture was cooled to 23 C., filtered, and concentrated under reduced pressure. The residue was recrystallized form Petroleum Ether:EtOAc (10:1) to afford 2-bromo-4-(bromomethyl)benzonitrile as a white solid (25 g, 60%). MS (ESI) m/z: 274 [M+H].sup.+.

Step B. 4-((1H-Benzo[d]imidazol-1-yl)methyl)-2-bromobenzonitrile

[0190] A mixture of 2-bromo-4-(bromomethyl)benzonitrile (2 g, 7.4 mmol), 1H-benzo[d]imidazole (1.05 g, 8.8 mmol), and K.sub.2CO.sub.3 (3.06 g, 22.2 mmol) in MeCN (30 mL) was heated at 40 C. for 3 hours. The reaction mixture was cooled, concentrated under reduced pressure and purified by chromatography using CH.sub.2Cl.sub.2:EtOAc (1:1) as eluting solvents to afford 4-((1H-benzo[d]imidazol-1-yl)methyl)-2-bromobenzonitrile as a yellow solid (1.2 g, 50%). MS (ESI) m/z: 312 [M+H].sup.+.

Step C. 5-((1H-Benzo[d]imidazol-1-yl)methyl)-4-methoxy-[1,1-biphenyl]-2-carbonitrile

[0191] A mixture of 4-((1H-benzo[d]imidazol-1-yl)methyl)-2-bromobenzonitrile (1.2 g, 3.8 mmol), 4-methoxyphenylboronic acid (0.53 g, 4.2 mmol), Pd(PPh.sub.3).sub.4 (0.037 g, 0.03 mmol), and K.sub.2CO.sub.3 (1.3 g, 9.6 mmol) in 1,4-dioxane (25 mL) and H.sub.2O (5 mL) was purged with nitrogen and heated at 80 C. overnight. The reaction mixture was concentrated under reduced pressure and the residue purified by silica gel chromatography using CH.sub.2Cl.sub.2:EtOAc (1:1) as eluting solvents to afford 5-((1H-benzo[d]imidazol-1-yl)methyl)-4-methoxy-[1,1-biphenyl]-2-carbonitrile as a yellow solid (1.5 g, 95%). .sup.1H NMR (500 MHz, CDCl.sub.3) (ppm) 7.96 (s, 1H), 7.79 (d, J=8 Hz, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.35 (d, J=9 Hz, 2H), 7.26-7.19 (m, 4H), 7.07 (d, J=8 Hz, 1H), 6.92-6.89 (m, 2H), 5.40 (s, 2H), 3.78 (s, 3H). MS (ESI) m/z: 340 [M+H].sup.+.

Step D. 5-((1H-Benzo[d]imidazol-1-yl)methyl)-4-hydroxy-[1,1-biphenyl]-2-carbonitrile

[0192] A mixture of 5-((1H-benzo[d]imidazol-1-yl)methyl)-4-methoxy-[1,1-biphenyl]-2-carbonitrile (1.3 g, 3.8 mmol) in HBr (48 wt. % in H.sub.2O, 20 mL) was heated at 120 C. for 1 hour in a microwave oven. The reaction mixture was concentrated under reduced pressure and basified by adding a saturated aqueous solution of NaHCO.sub.3 to afford 5-((1H-benzo[d]imidazol-1-yl)methyl)-4-hydroxy-[1,1-biphenyl]-2-carbonitrile as a white solid (0.62 g, 44%). .sup.1HNMR (500 MHz, DMSO-d.sub.6) (ppm) 8.47 (s, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.68-7.66 (m, 1H), 7.57-7.54 (m, 2H), 7.36 (d, J=9 Hz, 2H), 7.31-7.29 (m, 1H), 7.24-7.19 (m, 2H), 6.89 (d, J=8.5 Hz, 2H), 5.64 (s, 2H); MS (ESI) m/z: 326 [M+H].sup.+.

Step E. 5-((1H-Benzo[d]imidazol-1-yl)methyl)-2-cyano-[1,1-biphenyl]-4-yl sulfamate

E.1: Sulfamoyl Chloride

[0193] Caution: this experiment must be performed under a fume hood since a strong release of carbon dioxide and carbon monoxide occurs.

[0194] Chlorosulfonyl isocyanate (17.4 mL, 200 mmol) was introduced into a 250 mL round bottom flask. Under an inert atmosphere, formic acid (7.54 mL, 200 mmol) was slowly added followed by toluene (60 mL). The resulting mixture was stirred 10 hours at 23 C. The solvent was removed to dryness under reduced pressure to afford the final product as a crystalline solid (23 g, quantitative yield). The compound was used in the next steps without further purification.

E.2: 5-((1H-Benzo[d]imidazol-1-yl)methyl)-2-cyano-[1,1-biphenyl]-4-yl sulfamate

[0195] A mixture of 5-((1H-benzo[d]imidazol-1-yl)methyl)-4-hydroxy-[1,1-biphenyl]-2-carbonitrile (150 mg, 0.46 mmol) and sulfamoyl chloride (800 mg, 6.9 mmol) in DMA (8 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 5-((1H-benzo[d]imidazol-1-yl)methyl)-2-cyano-[1,1-biphenyl]-4-yl sulfamate as white solid (20 mg, 11%). .sup.1HNMR (500 MHz, CD.sub.3OD) (ppm) 8.26 (s, 1H), 7.71 (d, J=8 Hz, 1H), 7.61 (d, J=4 Hz, 1H), 7.48-7.46 (m, 2H), 7.35-7.32 (m, 4H), 7.26-7.24 (m, 1H), 7.20-7.18 (m, 4H), 5.58 (s, 2H); MS (ESI) m/z: 405 [M+H].sup.+.

Example 2

5-(1H-Benzo[d]imidazol-1-ylamino)-2-cyano-[1,1-biphenyl]-4-yl sulfamate

Step A. 1H-Benzo[d]imidazol-1-amine

[0196] To a solution of 1H-benzo[d]imidazole (11.8 g, 100 mmol) and KOH (16.8 g, 300 mmol) in water (50 mL) at 45 C. was slowly added a solution of aminooxysulfonic acid (20 g, 160 mmol) in H.sub.2O (80 mL), which pH was adjusted to about 7 with NaHCO.sub.3. The mixture was stirred for 10 minutes, cooled with ice-bath, stirred 0 C. for 15 minutes, and then heated at 55 C. for 30 minutes, filtered, and dried to afford 1H-benzo[d]imidazol-1-amine as a white solid (8 g, 62%). MS (ESI) m/z: 134 [M+H].sup.+.

Step B. 4-(1H-Benzo[d]imidazol-1-ylamino)-2-bromobenzonitrile

[0197] To a solution of t-BuOK (6.21 g, 55 mmol) in DMSO (50 mL) at 25 C. was added dry 1H-benzo[d]imidazol-1-amine (7.32 g, 55 mmol). After stirring for 30 minutes, 2-bromo-4-fluorobenzonitrile (2 g, 10 mmol) was slowly added and the mixture further stirred at 25 C. for 2 hours. The reaction mixture was quenched with water, filtered, concentrated under reduced pressure to afford the title compound as a white solid (3 g, 19%). MS (ESI) m/z: 313 [M+H].sup.+.

Step C. 5-(1H-Benzo[d]imidazol-1-ylamino)-4-methoxy-[1,1-biphenyl]-2-carbonitrile

[0198] A mixture of 4-(1H-benzo[d]imidazol-1-ylamino)-2-bromobenzonitrile (624 mg, 2 mmol), 4-methoxyphenylboronic acid (453 mg, 3 mmol), Pd(PPh.sub.3).sub.4 (115 mg, 0.10 mmol), and K.sub.2CO.sub.3 (550 g, 4 mmol) in 1,4-dioxane (15 mL) and H.sub.2O (5 mL) was purged with nitrogen and heated at 90 C. for 3 hours. The reaction mixture was cooled and filtered. The filtrate was evaporated, purified by silica gel chromatography using Petroleum Ether:EtOAc. The title compound was obtained as yellow solid (670 mg, 98%). MS (ESI) m/z: 341 [M+H].sup.+.

Step D. 5-(1H-Benzo[d]imidazol-1-ylamino)-4-hydroxy-[1,1-biphenyl]-2-carbonitrile

[0199] To a solution of 5-(1H-benzo[d]imidazol-1-ylamino)-4-methoxy-[1,1-biphenyl]-2-carbonitrile (280 mg, 0.82 mmol) in CH.sub.2Cl.sub.2 (5 mL) at 78 C. was added BBr.sub.3 (3.0 N, 1.7 mL, 5 mmol). The mixture was stirred at 20 C. for 20 hours. Then the mixture was quenched with water and its pH was adjusted to about 8 with an aqueous saturated solution of Na.sub.2CO.sub.3 to form a solid. After filtration and drying, the title compound was obtained as red solid (220 mg, 82%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 10.31 (s, 1H), 9.78 (s, 1H), 8.47 (s, 1H), 7.76-7.74 (m, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.34-7.26 (m, 5H), 6.84 (d, J=8.5 Hz, 2H), 6.51 (s, 1H), 6.42 (d, J=7.5 Hz, 1H); MS (ESI) m/z: 327[M+H].sup.+.

Step E. 5-(1H-Benzo[d]imidazol-1-ylamino)-2-cyano-[1,1-biphenyl]-4-yl sulfamate

[0200] The procedure described in Example 1 step E was repeated using 5-(1H-benzo[d]imidazol-1-ylamino)-4-hydroxy-[1,1-biphenyl]-2-carbonitrile (140 mg) to obtain the title compound as white solid (40 mg, 23%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 10.41 (s, 1H), 8.47 (s, 1H), 8.09 (s, 2H), 7.78-7.74 (m, 2H), 7.54 (d, J=8.5 Hz, 2H), 7.38 (d, J=9.0 Hz, 2H), 7.33-7.28 (m, 3H), 6.52 (s, 2H); MS (ESI) m/z: 406 [M+H].sup.+.

Example 3

2-Cyano-5-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)biphenyl-4-yl sulfamate

[0201] Compound of Example 3 was prepared in the same manner as described for compound of Example 1 starting from 2-bromo-4-(bromomethyl)benzonitrile and 2-methyl-1H-benzo[d]imidazole. The title compound was obtained as a white solid (30 mg). .sup.1HNMR (500 MHz, DMSO-d.sub.6) (ppm) 7.92 (d, J=8.5 Hz, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.57-7.55 (m, 1H), 7.48-7.46 (m, 1H), 7.42 (d, J=8.5 Hz, 2H), 7.36 (s, 1H), 7.15-7.19 (m, 3H), 5.65 (s, 2H), 2.53 (s, 3H); MS (ESI) m/z: 419 [M+H].sup.+.

Example 4

5-((1H-Benzo[d][1,2,3]triazol-1-yl)methyl)-2-cyano-[1,1-biphenyl]-4-yl sulfamate

Step A. 4-((1H-Benzo[d][1,2,3]triazol-1-yl)methyl)-2-bromobenzonitrile

[0202] A solution of 2-bromo-4-(bromomethyl)benzonitrile (2.5 g, 9 mmol) [Example 1 Step A], 1H-benzo[d][1,2,3]triazole (1.1 g, 10 mmol), and K.sub.2CO.sub.3 (3.8 g, 27 mmol) in CH.sub.3CN (50 mL) was stirred for 12 hours at 25 C. The reaction mixture was cooled to 0 C., filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (30:1 to 3:1) as eluting solvents to afford 4-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-2-bromobenzonitrile as a yellow solid (1.52 g, 53%). MS (ESI) m/z: 313 [M+H].sup.+.

Step B. 5-((1H-Benzo[d][1,2,3]triazol-1-yl)methyl)-2-cyano-[1,1-biphenyl]-4-yl sulfamate

[0203] The procedures described in Example 2 steps C, D and E were repeated using 4-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-2-bromobenzonitrile to obtain the title compound as a yellow solid (38 mg, 27%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.14 (brs, 2H), 8.08 (d, J=8.5 Hz, 1H), 7.95 (d, J=8 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.65 (d, J=9 Hz, 2H), 7.62 (s, 1H), 7.58 (t, 1H), 7.43 (d, J=8.5 Hz, 2H), 7.42 (d, J=6 Hz, 2H), 6.13 (s, 2H); MS (ESI) m/z: 406 [M+H].sup.+.

Example 5

5-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-2-cyano-[1,1-biphenyl]-4-yl sulfamate

Step A. 5-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-4-methoxy-[1,1-biphenyl]-2-carbonitrile

[0204] To a solution of NaH (60 mg, 1.50 mmol) in THF (7 mL) at 0 C. was added 5-(1H-benzo[d]imidazol-1-ylamino)-4-methoxy-[1,1-biphenyl]-2-carbonitrile (340 mg, 1 mmol) [Example 2 Step C]. The mixture was stirred for 15 minutes before addition, at 0 C., of iodomethane (284 mg, 2 mmol) in a dropwise manner. After a 2-hour stirring at 25 C., the reaction mixture was quenched with MeOH and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the title compound as a white solid (300 mg, 84%). MS (ESI) m/z: 355 [M+H].sup.+.

Step B. 5-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-2-cyano-[1,1-biphenyl]-4-yl sulfamate

[0205] The procedures described in Example 2 steps D and E were repeated using 5-((1H-benzo[d]imidazol-1-yl)(methyl)amino)-4-methoxy-[1,1-biphenyl]-2-carbonitrile (170 mg) to obtain the title compound as white solid (120 mg, 57%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.58 (s, 1H), 7.79-7.77 (m, 2H), 7.59 (d, J=8.5 Hz, 2H), 7.40-7.30 (m, 6H), 6.69 (d, J=2.0 Hz, 1H), 6.50-6.48 (m, 1H), 3.64 (s, 3H); MS (ESI) m/z: 420 [M+H].sup.+.

Example 6

5-((1H-Benzo[d]imidazol-1-yl)(cyclopropylmethyl)amino)-2-cyano-[1,1-biphenyl]-4-yl sulfamate

[0206] Compound of Example 6 was prepared in the same manner as described for compound of Example 5 starting from 5-(1H-benzo[d]imidazol-1-ylamino)-4-methoxy-[1,1-biphenyl]-2-carbonitrile [Example 2 Step C] and (bromomethyl)cyclopropane. The title compound was obtained as white solid (150 mg). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.55 (s, 1H), 8.11 (s, 2H), 7.79-7.76 (m, 2H), 7.59 (d, J=9.0 Hz, 2H), 7.40-7.28 (m, 5H), 6.72 (d, J=2.5 Hz, 1H), 6.54-6.52 (m, 1H), 4.02-3.97 (m, 1H), 3.8-3.76 (m, 1H), 0.86-0.82 (m, 1H), 0.33 (d, J=8.0 Hz, 2H), 0.12-0.10 (m, 1H), 0.01-0.04 (m, 1H); MS (ESI) m/z: 460 [M+H].sup.+.

Example 7

2-Cyano-5-((2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)biphenyl-4-yl sulfamate

[0207] Compound of Example 7 was prepared in the same manner as described for compound of Example 1 starting from 2-bromo-4-(bromomethyl)benzonitrile and 2-(trifluoromethyl)-1H-benzo[d]imidazole. The title compound was obtained as a gray solid (30 mg, 17%). .sup.1HNMR (500 MHz, DMSO-d.sub.6) (ppm) 8.14 (s, 2H), 7.93-7.89 (m, 2H), 7.73 (d, J=8 Hz, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.47 (d, J=7.5 Hz, 1H), 7.44-7.41 (m, 4H), 7.11 (d, J=8 Hz, 1H), 5.89 (s, 2H); MS (ESI) m/z: 473 [M+H].sup.+.

Example 8

5-((3H-[1,2,3]Triazolo[4,5-b]pyridin-3-yl)methyl)-2-cyano-[1,1-biphenyl]-4-yl sulfamate

Step A. 2-Bromo-4-((1,3-dioxoisoindolin-2-yl)methyl)benzonitrile

[0208] A solution of 2-bromo-4-(bromomethyl)benzonitrile (25 g, 90 mmol) and potassium phthalimide (18 g, 97 mmol) in DMF (200 mL) was stirred at 60 C. for 3 hours. The reaction mixture was cooled to room temperature and poured into water (1 L). The precipitate thus formed was filtered and the filter cake was collected to afford a crude 2-bromo-4-((1,3-dioxoisoindolin-2-yl)methyl)benzonitrile as a white solid, which was used without further purification. MS (ESI) m/z: 341 [M+H].sup.+.

Step B. 4-(Aminomethyl)-2-bromobenzonitrile

[0209] A solution of 2-bromo-4-((1,3-dioxoisoindolin-2-yl)methyl)benzonitrile (crude product) and hydrazine hydrate (38 mL) in EtOH (500 mL) was heated at reflux for 2 hours. The reaction mixture was cooled, filtered, and concentrated under reduced pressure to afford a crude 4-(aminomethyl)-2-bromobenzonitrile as yellow solid, which was used without further purification. MS (ESI) m/z: 211 [M+H].sup.+.

Step C. 2-Bromo-4-((3-nitropyridin-2-ylamino)methyl)benzonitrile

[0210] To a solution of 4-(aminomethyl)-2-bromobenzonitrile in dry t-BuOH (200 mL) at 25 C., was added sodium (6.3 g) in several small portions. After the mixture was stirred at 50 C. for 0.5 hour, 2-chloro-3-nitropyridine (14 g, 89 mmol) was added in several portions. The reaction mixture was heated at reflux for 3 hours and concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (10:1 to 5:1) as eluting solvents to afford 2-bromo-4-((3-nitropyridin-2-ylamino)methyl)benzonitrile as a red solid (7.5 g, 27% for 3 steps). MS (ESI) m/z: 332 [M+H].sup.+.

Step D. 4-((3-Aminopyridin-2-ylamino)methyl)-2-bromobenzonitrile

[0211] To a solution of 2-bromo-4-((3-nitropyridin-2-ylamino)methyl)benzonitrile (7.5 g, 23 mmol) in EtOH (50 mL) and H.sub.2O (30 mL) at reflux, was added iron powder (3.8 g, 69 mmol) and NH.sub.4Cl (12 g, 222 mmol). The mixture was heated one more hour under reflux before cooling to 25 C. and filtration through a celite cake. After concentration under reduced pressure, the crude 4-((3-aminopyridin-2-ylamino)methyl)-2-bromobenzonitrile was obtained and used in the next step without further purification. MS (ESI) m/z: 303 [M+H].sup.+.

Step E. 4-((3H-[1,2,3]Triazolo[4,5-b]pyridin-3-yl)methyl)-2-bromobenzonitrile

[0212] A solution of 4-((3-aminopyridin-2-ylamino)methyl)-2-bromobenzonitrile in concentrated HCl (50 mL) in an ice bath was treated with sodium nitrite (1.7 g, 24 mmol). The mixture was stirred at 5 C. for 1 hour before adding an ammonium hydroxide solution until pH >7. After extraction with EtOAc (50 mL*3), the combined organic extracts were concentrated under reduced pressure. The residue was purified by silica gel chromatography Petroleum Ether:EtOAc (10:1 to 5:1) to afford 4-((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)-2-bromobenzonitrile as a yellow solid (1.5 g, 21% for two steps). MS (ESI) m/z: 314 [M+H].sup.+.

Step F. 5-((3H-[1,2,3]Triazolo[4,5-b]pyridin-3-yl)methyl)-2-cyano-[1, 1-biphenyl]-4-yl sulfamate

[0213] The procedures described in Example 2 steps C, D and E were repeated with 4-((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)-2-bromobenzonitrile to obtain the title compound as white solid (55 mg, 13%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.80 (dd, J.sub.1=1.5 Hz, J.sub.2=4.5 Hz, 1H), 8.63 (dd, J.sub.1=2 Hz, J.sub.2=8.5 Hz, 1H), 8.17 (brs, 2H), 7.95 (d, J=8.5 Hz, 1H), 7.66 (d, J=5 Hz, 2H), 7.65 (s, 1H), 7.47 (dd, J.sub.1=1.5 Hz, J.sub.2=8 Hz, 1H), 7.45 (d, J=5 Hz, 2H), 7.43 (d, J=5 Hz, 1H), 6.47 (s, 2H). MS (ESI) m/z: 407 [M+H].sup.+.

Example 9

4-(2-((1H-Benzo[d]imidazol-1-yl)methyl)-5-cyanopyrimidin-4-yl)phenyl sulfamate

Step A. 2-(1H-Benzo[d]imidazol-1-yl)acetonitrile

[0214] A mixture of 1H-benzo[d]imidazole (5.9 g, 50 mmol), ClCH.sub.2CN (4.55 g, 60 mmol), and K.sub.2CO.sub.3 (13.8 g, 100 mmol) in MeCN (50 mL) was heated at 40 C. for 3 hours. The reaction mixture was cooled to 25 C., concentrated under reduced pressure and purified by silica gel chromatography using CH.sub.2Cl.sub.2:MeOH (150:1) as eluting solvents to afford 2-(1H-benzo[d]imidazol-1-yl)acetonitrile as a gray solid (5.5 g, 70%). MS (ESI) m/z: 158 [M+H].sup.+.

Step B. 2-(1H-Benzo[d]imidazol-1-yl)acetimidamide

[0215] A mixture of 2-(1H-benzo[d]imidazol-1-yl)acetonitrile (1 g, 6.37 mmol) and MeONa (0.034 g, 0.64 mmol) in THF (20 mL) and MeOH (20 mL) was heated at 45 C. overnight. After the reaction mixture was cooled to 25 C., NH.sub.4Cl (0.68 g, 12.74 mmol) was added followed by MeOH (10 mL). The mixture was stirred at 80 C. for 4 hours, quenched by H.sub.2O (5 mL), concentrated under reduced pressure, and recrystallized by H.sub.2O and EtOH to afford 2-(1H-benzo[d]imidazol-1-yl)acetimidamide as a gray solid (800 mg, 72%). MS (ESI) m/z: 175 [M+H].sup.+.

Step C. (E)-3-(Dimethylamino)-2-(4-methoxybenzoyl)acrylonitrile

[0216] A solution of 3-(4-methoxyphenyl)-3-oxopropanenitrile (1.6 g, 9.1 mmol) and N,N-dimethylformamide dimethylacetal (1.59 g, 11 mmol) in toluene (15 mL) was stirred at 50 C. for 1 hour. The reaction mixture was cooled and concentrated to afford the crude (E)-3-(dimethylamino)-2-(4-methoxybenzoyl)acrylonitrile as a yellow solid (1.8 g, 86%). MS (ESI) m/z: 231 [M+H].sup.+.

Step D. 2-((1H-Benzo[d]imidazol-1-yl)methyl)-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile

[0217] A mixture of (E)-3-(dimethylamino)-2-(4-methoxybenzoyl)acrylonitrile (230 mg, 1 mmol), 2-(1H-benzo[d]imidazol-1-yl)acetimidamide (174 mg, 1 mmol), and DIPEA (387 mg, 3 mmol) in 2-pentanol (10 mL) was heated at 130 C. for 3 hours. The reaction mixture was cooled, concentrated under reduced pressure and purified by silica gel chromatography using CH.sub.2Cl.sub.2:MeOH (80:1) as eluting solvents to afford 2-((1H-benzo[d]imidazol-1-yl)methyl)-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile as a yellow solid (300 g, 73%). MS (ESI) m/z: 342 [M+H].sup.+.

Step E. 4-(2-((1H-Benzo[d]imidazol-1-yl)methyl)-5-cyanopyrimidin-4-yl)phenyl sulfamate

[0218] The procedures described in Example 2 steps D and E were repeated using 2-((1H-benzo[d]imidazol-1-yl)methyl)-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile (230 mg) to obtain the title compound as a white solid (34 mg, 12%). .sup.1HNMR (500 MHz, DMSO-d.sub.6) (ppm) 9.33 (s, 1H), 8.37 (s, 1H), 8.22 (s, 2H), 8.00 (d, J=9 Hz, 2H), 7.69-7.68 (m, 1H), 7.52-7.48 (m, 3H), 7.22-7.21 (m, 2H), 5.93 (s, 2H); MS (ESI) m/z: 407 [M+H].sup.+.

Example 10

4-(6-((1H-Benzo[d]imidazol-1-yl)methyl)-3-cyanopyridin-2-yl)phenyl sulfamate

Step A. 6-(Bromomethyl)-2-chloronicotinonitrile

[0219] A solution of 2-chloro-6-methylnicotinonitrile (42 g, 276 mmol), benzoyl peroxide (6.7 g, 27.6 mmol), and NBS (62 g, 276.3 mmol) in CCl.sub.4 (800 mL) was stirred for 4 hours at 85 C. The reaction mixture was cooled to 25 C., filtered, and concentrated under reduced pressure. The residue was recrystallized from Petroleum Ether:EtOAc (10:1) to afford 6-(bromomethyl)-2-chloronicotinonitrile as a white solid (19 g, 30%). MS (ESI) m/z: 231 [M+H].sup.+.

Step B. 6-((1H-Benzo[d]imidazol-1-yl)methyl)-2-chloronicotinonitrile

[0220] A solution of 6-(bromomethyl)-2-chloronicotinonitrile (2.32 g, 10 mmol), 1H-benzo[d]imidazole (1.2 g, 10 mmol), and K.sub.2CO.sub.3 (4 g, 30 mmol) in CH.sub.3CN (150 mL) was stirred at 25 C. for 20 hours. The reaction mixture was cooled, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using MeOH: CH.sub.2Cl.sub.2 (1:200-1:30) to afford 6-((1H-benzo[d]imidazol-1-yl)methyl)-2-chloronicotinonitrile as a yellow oil (300 mg, 11%). MS (ESI) m/z: 269 [M+H].sup.+.

Step C. 4-(6-((1H-Benzo[d]imidazol-1-yl)methyl)-3-cyanopyridin-2-yl)phenyl sulfamate

[0221] The procedures described in Example 2 steps C, D and E were repeated using 6-(bromomethyl)-2-chloronicotinonitrile to obtain the title compound as a white solid (80 mg, 20%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.42-8.41 (m, 2H), 8.16 (s, 1H), 7.88-7.86 (m, 2H), 7.69-7.67 (m, 2H), 7.56-7.54 (m, 1H), 7.45-7.40 (m, 3H), 7.24-7.21 (m, 2H), 5.78 (s, 2H); MS (ESI) m/z: 406 [M+H].sup.+.

Example 11

5-(1H-Benzo[d][1,2,3]triazol-1-ylamino)-2-cyanobiphenyl-4-yl sulfamate

Step A. 1H-Benzo[d][1,2,3]triazol-1-amine

[0222] To a solution of benzotriazole (5 g, 42.01 mmol) and potassium hydroxide (11.76 g, 0.21 mol) in water (50 mL) was added hydroxylamine-O-sulfonic acid (9.49 g, 84.02 mmol) in several portions and the temperature of the reaction mixture was kept below 50 C. After the addition, the mixture was stirred at room temperature for 2 hours. The resulting precipitate was removed by filtration and washed thoroughly with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (300:1) as eluting solvents to afford 1H-benzo[d][1,2,3]triazol-1-amine as a white solid (1.52 g, 27%). MS (ESI) m/z: 135 [M+H].sup.+.

Step B. 5-(1H-Benzo[d][1,2,3]triazol-1-ylamino)-2-cyanobiphenyl-4-yl sulfamate

[0223] The procedures described in Example 2 Step C, D and E were repeated using 1H-benzo[d][1,2,3]triazol-1-amine to obtain the title compound as a white solid (60 mg). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 11.19 (s, 1H), 8.18 (d, 1H), 8.12 (s, 2H), 7.79 (d, 1H), 7.66 (m, 2H), 7.57 (m, 2H), 7.52 (m, 1H), 7.40 (m, 2H), 6.58 (d, 1H), 6.48 (dd, 1H); MS (ESI) m/z: 407 [M+H].sup.+.

Example 12

5-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-2-cyano-[1,1-biphenyl]-4-yl sulfamate

Step A. 4-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-2-bromobenzonitrile

[0224] A mixture of 3H-imidazo[4,5-b]pyridine (835 mg, 7 mmol), 2-bromo-4-(bromomethyl)benzonitrile (410 mg 3.4 mmol), K.sub.2CO.sub.3 (938 mg, 6.8 mmol), and KI (113 mg, 0.68 mmol) in CH.sub.3CN was stirred at room temperature for 12 hours. The reaction mixture was quenched with EtOAc, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using CH.sub.2Cl.sub.2:methanol (30:1) as eluting solvents to afford 4-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-bromobenzonitrile as a white solid (1.14 g, 52%). MS (ESI) m/z: 313 [M+H].sup.+.

Step B. 5-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-2-cyano-[1,1-biphenyl]-4-yl sulfamate

[0225] The procedures described in Example 2 steps C, D and E were repeated using 4-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-bromobenzonitrile to obtain the title compound as a yellow solid (40 mg, 10%). .sup.1H NMR (500 MHz, DMSO-d) (ppm) 9.68 (s, 1H), 8.37 (d, J=6.5 Hz, 1H), 8.13-8.11 (m, 3H), 7.94 (d, J=5 Hz, 1H), 7.65-7.61 (m, 3H), 7.47-7.42 (m, 3H), 7.31 (m, 1H), 5.67 (s, 2H); MS (ESI) m/z: 406 [M+H].sup.+.

Example 13

5-((1H-Benzo[d][1,2,3]triazol-1-yl)(methyl)amino)-2-cyanobiphenyl-4-yl sulfamate

Step A. 4-((1H-Benzo[d][1,2,3]triazol-1-yl)(methyl)amino)-2-bromobenzonitrile

[0226] The procedure described in Example 5 step A was repeated using 4-(1H-benzo[d][1,2,3]triazol-1-ylamino)-2-bromobenzonitrile (563 mg, 1.79 mmol) to obtain the title compound as a white solid (570 mg, 97%). MS (ESI) m/z: 328 [M+H].sup.+.

Step B. 5-((1H-Benzo[d][1,2,3]triazol-1-yl)(methyl)amino)-2-cyanobiphenyl-4-yl sulfamate

[0227] The procedures described in Example 2 steps C, D and E were repeated using 4-((1H-benzo[d][1,2,3]triazol-1-yl)(methyl)amino)-2-bromobenzonitrile to obtain the title compound as a white solid (31 mg). .sup.1H NMR (500 MHz, CDCl.sub.3) (ppm) 8.17 (d, 1H), 7.58-7.64 (m, 2H), 7.47-7.51 (m, 4H), 7.38-7.40 (m, 2H), 6.52 (m, 2H), 5.04 (s, 2H), 3.70 (s, 3H); MS (ESI) m/z: 421 [M+H].sup.+.

Example 14

4-(6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-3-cyanopyridin-2-yl)phenyl sulfamate

Step A. 6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-2-chloronicotinonitrile

[0228] A solution of 6-(bromomethyl)-2-chloronicotinonitrile (2.32 g, 10 mmol) [Example 10 step A], 3H-imidazo[4,5-b]pyridine (1.3 g, 11 mmol), and K.sub.2CO.sub.3 (4 g, 30 mmol) in CH.sub.3CN (40 mL) was stirred at 25 C. for 20 hours. The reaction mixture was cooled to 25 C., filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (5:1-1:1) to afford the title compound as a yellow oil (600 mg, 30%). MS (ESI) m/z: 270 [M+H].sup.+.

Step B. 4-(6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-3-cyanopyridin-2-yl)phenyl sulfamate

[0229] The procedures described in Example 2 steps C, D and E were repeated using 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-chloronicotinonitrile to obtain the title compound as white solid (105 mg, 47%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.64 (s, 1H), 8.41 (d, J=8.0 Hz, 1H), 8.33-8.32 (m, 1H), 8.14-8.12 (m, 1H), 7.82-7.80 (m, 4H), 7.45 (d, J=8.5 Hz, 1H), 7.42-7.40 (m, 3H), 7.32-7.30 (m, 1H), 5.80 (s, 2H); MS (ESI) m/z: 407 [M+H].sup.+.

Example 15

4-(2-(1H-Benzo[d]imidazol-1-ylamino)-5-cyanopyrimidin-4-yl)phenyl sulfamate

Step A. 2-Imino-4-(4-methoxyphenyl)-1,2-dihydropyrimidine-5-carbonitrile

[0230] A solution of (E)-3-(dimethylamino)-2-(4-methoxybenzoyl)acrylonitrile (500 mg, 2.2 mmol), guanidine hydrochloride (627 mg, 6.6 mmol), and K.sub.2CO.sub.3 (1.82 g, 13.2 mmol) in DMF (15 mL) was stirred at 70 C. for 20 hours. The reaction mixture was quenched with water (20 mL) and filtered. The solid was dried to afford the 2-imino-4-(4-methoxyphenyl)-1,2-dihydropyrimidine-5-carbonitrile as a yellow solid (400 mg, 80%). MS (ESI) m/z: 227 [M+H].sup.+.

Step B. 2-Hydroxy-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile

[0231] A solution of 2-imino-4-(4-methoxyphenyl)-1,2-dihydropyrimidine-5-carbonitrile (2.4 g, 10.6 mmol) in AcOH (30 mL) was heated to 70 C., then NaNO.sub.2 (5.4 g, 31.8 mmol) in water (10 mL) was added slowly. The mixture was stirred at 70 C. for 20 hours and then quenched with water (20 mL), extracted with EtOAC (200 mL3), washed with brine and dried (Na.sub.2SO.sub.4). After filtration and evaporation, the residue was crystallized in EtOAc to afford 2-hydroxy-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile as a yellow solid (1.9 g, 79%). MS (ESI) m/z: 228 [M+H].sup.+.

Step C. 2-Chloro-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile

[0232] A solution of 2-hydroxy-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile (1.6 g, 7 mmol) in POCl.sub.3 (30 mL) was heated at 100 C. for 20 hours, then quenched with ice-water slowly and adjusted to pH=4. The mixture was filtered to afford 2-chloro-4-(4-methoxyphenyl) pyrimidine-5-carbonitrile as a yellow solid (1.1 g, 65%). MS (ESI) m/z: 246 [M+H].sup.+.

Step D. 2-(1H-Benzo[d]imidazol-1-ylamino)-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile

[0233] A solution of 2-chloro-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile (900 mg, 3.7 mmol), 1H-benzo[d]imidazol-1-amine (532 mg, 4 mmol), Cs.sub.2CO.sub.3 (2.4 g, 7.4 mmol), Pd.sub.2(dba).sub.3 (200 mg, 0.185 mmol) and Xantphos (384 mg, 0.29 mmol) in 1,4-dioxane (20 mL) under N.sub.2 was heated at 90 C. for 20 hours. After cooling to 25 C., the mixture was evaporated under reduced pressure and the residue purified by silica gel chromatography using Petroleum Ether:EtOAc (10:1-1:1) to afford 2-(1H-benzo[d]imidazol-1-ylamino)-4-(4-methoxyphenyl) pyrimidine-5-carbonitrile as a yellow solid (270 mg, 21%). MS (ESI) m/z: 343 [M+H].sup.+.

Step E. 4-(2-(1H-Benzo[d]imidazol-1-ylamino)-5-cyanopyrimidin-4-yl)phenyl sulfamate

[0234] The procedures described in Example 2 steps D and E were repeated using starting with 2-(1H-benzo[d]imidazol-1-ylamino)-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile (120 mg) to obtain the title compound as a white solid (27 mg, 18%). .sup.1H NMR (500 MHz, CD.sub.3OD) (ppm) 8.85 (brs, 1H), 8.34 (s, 1H), 7.77-7.75 (m, 2H), 7.65-7.60 (m, 1H), 7.50-7.36 (m, 5H); MS (ESI) m/z: 408 [M+H].sup.+.

Example 16

4-(2-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-5-cyanopyrimidin-4-yl)phenyl sulfamate

Step A. 2-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile

[0235] The procedure described in Example 5 step A was repeated using 2-(1H-benzo[d]imidazol-1-ylamino)-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile (240 mg) and iodomethane, the title compound was obtained as a yellow solid (210 mg, 84%). MS (ESI) m/z: 357 [M+H].sup.+.

Step B. 4-(2-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-5-cyanopyrimidin-4-yl)phenyl sulfamate

[0236] The procedures described in Example 2 steps D and E were repeated using 2-((1H-benzo[d]imidazol-1-yl)(methyl)amino)-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile (110 mg) to obtain the title compound as a white solid (17 mg). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.90 (brs, 1H), 8.54 (s, 1H), 8.25 (brs, 3H), 7.77-7.29 (m, 7H), 3.84 (s, 3H); MS (ESI) m/z: 422 [M+H].sup.+.

Example 17

4-(2-((1H-Benzo[d]imidazol-1-yl)methyl)-5-cyanopyridin-4-yl)phenyl sulfamate

Step A. 4-Chloro-6-methylnicotinonitrile

[0237] A solution of 4-hydroxy-6-methylnicotinamide (5 g, 32 mmol) and PCl.sub.5 (10.3 g, 50 mmol) in POCl.sub.3 (50 mL) was heated to reflux for 20 hours. The reaction mixture was cooled to 25 C. and concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum ether:EtOAc (3:1) as eluting solvents to afford 4-chloro-6-methylnicotinonitrile as white solid (3.2 g, 64%). MS (ESI) m/z: 153 [M+H]+

Step B. 6-(Bromomethyl)-4-chloronicotinonitrile

[0238] A mixture of 4-chloro-6-methylnicotinonitrile (3.2 g, 21 mmol), NBS (3.7 g, 21 mmol), and benzoyl peroxide (968 mg, 4 mmol) in CCl.sub.4 (50 mL) under nitrogen was heated to reflux for 12 hours. The mixture was cooled to 25 C., filtered and the filtrate was concentrated under reduced pressure. The residue was use in the next step without further purification. MS (ESI) m/z: 231 [M+H].sup.+.

Step C. 4-((1H-Benzo[d]imidazol-1-yl)methyl)-2-chlorobenzonitrile

[0239] A mixture of 6-(bromomethyl)-4-chloronicotinonitrile (1.8 g, 7.8 mmol), 1H-imidazo[4,5-c]pyridine (929 mg 7.8 mmol), K.sub.2CO.sub.3 (2 g, 15.6 mmol), and KI (266 mg, 1.6 mmol) in CH.sub.3CN was stirred at 25 C. for 12 hours. The reaction mixture was diluted with EtOAc, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using CH.sub.2Cl.sub.2:methanol (30:1) as eluting solvents to afford 4-((1H-benzo[d]imidazol-1-yl)methyl)-2-chloro-benzonitrile as light yellow solid (833 mg, 40%). MS (ESI) m/z: 268 [M+H].sup.+.

Step D. 4-(2-((1H-Benzo[d]imidazol-1-yl)methyl)-5-cyanopyridin-4-yl)phenyl sulfamate

[0240] The procedures described in Example 2 steps C, D and E were repeated using 4-((1H-benzo[d]imidazol-1-yl)methyl)-2-chlorobenzonitrile to obtain the title compound as light yellow solid (40 mg, 10%). .sup.1H NMR (500 MHz, DMSO-d) (ppm) 9.04 (s, 1H), 8.40 (s, 1H), 8.19 (s, 2H), 7.78-7.56 (m, 2H), 7.73 (m, 1H), 7.67 (m, 1H), 7.54 (m, 1H), 7.50-7.48 (m, 2H), 7.21-7.20 (m, 2H), 5.76 (s, 2H); MS (ESI) m/z: 406 [M+H].sup.+.

Example 18

5-((1H-Benzo[d]imidazol-1-yl)methyl)-2-cyano-3-(methylthio)-[1,1-biphenyl]-4-yl sulfamate

Step A. (5-Bromo-2-methoxyphenyl)(methyl)sulfane and (4-Bromo-2-methoxyphenyl)(methyl)sulfane

[0241] To a solution of 2-methylthioanisole (2 g, 13 mmol) in CH.sub.2Cl.sub.2 (50 mL) was added powdered Fe (0.73 g, 1.3 mmol), followed by a dropwise addition of bromine (2.1 g, 13 mmol). After stirred at room temperature for 30 minutes, the starting material had been consumed. The excess bromine was quenched by adding a saturated aqueous solution of NaHSO.sub.3 and the mixture was stirred for several minutes. The CH.sub.2Cl.sub.2 layer was separated, and the aqueous phase extracted with CH.sub.2Cl.sub.2. The combined CH.sub.2Cl.sub.2 extracts were dried over MgSO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatograph using Petroleum Ether to afford a mixture of (5-bromo-2-methoxyphenyl)(methyl)sulfane and (4-bromo-2-methoxyphenyl)(methyl)sulfane as a yellow oil. (1.2 g, 40%). MS (ESI) m/z: 234 [M+H].sup.+.

Step B. 2-(4-Methoxy-3-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 2-(3-Methoxy-4-(methylthio)phenyl)-4,4,5,5-tetra methyl-1,3,2-dioxaborolane

[0242] A mixture of (5-bromo-2-methoxyphenyl)(methyl)sulfane and (4-bromo-2-methoxyphenyl)(methyl)sulfane (1100 mg, 4.72 mmol), 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (1439 mg, 5.66 mmol), KOAc (925 mg, 9.44 mmol) and Pd(dppf)Cl.sub.2 (193 mg, 0.24 mmol) in 1,4-dioxane (50 mL) and DMSO (2 mL) was purged with nitrogen and heated at 90 C. for 14 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether as eluting solvents to afford a mixture of 2-(4-methoxy-3-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 2-(3-methoxy-4-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a white solid (1196 mg, 90%). MS (ESI) m/z: 281 [M+H].sup.+.

Step C. 5-((1H-Benzo[d]imidazol-1-yl)methyl)-4-methoxy-3-(methylthio)-[1,1-biphenyl]-2-carbonitrile and 5-((1H-benzo[d]imidazol-1-yl)methyl)-3-methoxy-4-(methylthio)-[1,1-biphenyl]-2-carbonitrile

[0243] A mixture of 4-((1H-benzo[d]imidazol-1-yl)methyl)-2-bromobenzonitrile (312 mg, 1 mmol), 2-(4-methoxy-3-(methylthio)phenyl)-4,4,5,5-tetra methyl-1,3,2-dioxaborolane/2-(3-methoxy-4-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (290 mg, 1.05 mmol), K.sub.2CO.sub.3 (276 mg, 2 mmol), and Pd(PPh.sub.3).sub.4 (58 mg, 0.05 mmol) in 1,4-dioxane (6 mL) and H.sub.2O (1.2 mL) was purged with nitrogen and heated at 90 C. for 14 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using CH.sub.2Cl.sub.2:MeOH (50:1) as eluting solvents to afford a mixture of 5-((1H-benzo[d]imidazol-1-yl)methyl)-4-methoxy-3-(methylthio)-[1,1-biphenyl]-2-carbonitrile and 5-((1H-benzo[d]imidazol-1-yl)methyl)-3-methoxy-4-(methylthio)-[1,1-biphenyl]-2-carbonitrile as a yellow solid (349 mg, 90.6%). MS (ESI) m/z: 386 [M+H].sup.+.

Step D. 5-((1H-Benzo[d]imidazol-1-yl)methyl)-4-hydroxy-3-(methylthio)-[1,1-biphenyl]-2-carbonitrile and 5-((1H-benzo[d]imidazol-1-yl)methyl)-3-hydroxy-4-(methylthio)-[1,1-biphenyl]-2-carbonitrile

[0244] A mixture of 5-((1H-benzo[d]imidazol-1-yl)methyl)-4-methoxy-3-(methylthio)-[1,1-biphenyl]-2-carbonitrile and 5-((1H-benzo[d]imidazol-1-yl)methyl)-3-methoxy-4-(methylthio)-[1,1-biphenyl]-2-carbonitrile (349 mg, 0.91 mmol) in CH.sub.2Cl.sub.2 (40 mL) was cooled to 78 C. during the addition of BBr.sub.3 (2 mL, 22 mmol). The reaction mixture was stirred at 23 C. for 4 hours before being poured into water where pH was adjusted to 7 with dry NaHCO.sub.3. The organic layer was decanted and the aqueous layer was extracted with CH.sub.2Cl.sub.2 (40 mL2). The organic solutions were collected, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column using Petroleum Ether: EtOAc (1:1) and by preparative HPLC to afford 5-((1H-benzo[d]imidazol-1-yl)methyl)-4-hydroxy-3-(methylthio)-[1,1-biphenyl]-2-carbonitrile as a white solid (120 mg, 35.5%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 10.39 (s, 1H), 8.47 (s, 1H), 7.89-7.88 (d, J=8.0 Hz, 1H), 7.70-7.67 (d, J=7.0 Hz, 1H), 7.56-7.55 (d, J=7.0 Hz, 1H), 7.52 (s, 1H), 7.38-7.36 (d, J=8.0 Hz, 1H), 7.23-7.20 (m, 3H), 6.96-6.94 (d, J=8.0 Hz, 1H), 6.93 (s, 1H), 5.66 (s, 2H), 2.41 (s, 3H); MS (ESI) m/z: 372 [M+H]+ and 5-((1H-benzo[d]imidazol-1-yl)methyl)-3-hydroxy-4-(methylthio)-[1,1-biphenyl]-2-carbonitrile as a white solid (70 mg, 20.7%). MS (ESI) m/z: 372 [M+H].sup.+.

Step E. 5-((1H-Benzo[d]imidazol-1-yl)methyl)-2-cyano-3-(methylthio)-[1,1-biphenyl]-4-yl sulfamate

[0245] A mixture of 5-((1H-benzo[d]imidazol-1-yl)methyl)-4-hydroxy-3-(methylthio)-[1,1-biphenyl]-2-carbonitrile (100 mg, 0.27 mmol) and sulfamoyl chloride (310 mg, 2.7 mmol) [see Example 1 step E] in DMA (5 mL) was stirred overnight at 23 C. The solution was concentrated under reduced pressure and the residue was purified by preparative HPLC to afford 5-((1H-benzo[d]imidazol-1-yl)methyl)-2-cyano-3-(methylthio)-[1,1-biphenyl]-4-yl sulfamate as a white solid (40 mg, 33%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.48 (s, 1H), 8.28 (s, 2H), 7.95-7.93 (d, J=8.0 Hz, 1H), 7.68-7.65 (m, 2H), 7.59-7.57 (d, J=6.9 Hz, 1H), 7.51-7.49 (d, J=8.4 Hz, 1H), 7.45-7.42 (m, 2H), 7.38-7.36 (d, J=8.4 Hz, 1H), 7.25-7.18 (m, 2H), 5.67 (s, 2H), 2.47 (s, 3H); MS (ESI) m/z: 451 [M+H].sup.+.

Example 19

5-((1H-benzo[d]imidazol-1-yl)methyl)-2-cyano-4-(methylthio)-[1,1-biphenyl]-3-yl sulfamate

[0246] Compound of Example 19 was prepared in the same manner as described for compound of Example 18 starting from 5-((1H-benzo[d]imidazol-1-yl)methyl)-3-hydroxy-4-(methylthio)-[1,1-biphenyl]-2-carbonitrile. The title compound was obtained as a white solid (16 mg, 18.8%). .sup.1H NMR (500 MHz, CD.sub.3OD) (ppm) 8.37 (s, 1H), 7.83-7.81 (d, J=8.0 Hz, 1H), 7.73-7.71 (m, 1H), 7.61 (s, 1H), 7.55 (s, 1H), 7.50-7.45 (m, 3H), 7.34-7.30 (m, 3H), 5.69 (s, 2H), 2.53 (s, 3H); MS (ESI) m/z: 451 [M+H].sup.+.

Example 20

5-((1H-Benzo[d]imidazol-1-yl)amino)-2-cyano-3-(methylthio)-[1,1-biphenyl]-4-yl sulfamate

[0247] Compound of Example 20 was prepared in the same manner as described for compound of Example 18 starting from a mixture of 2-(4-methoxy-3-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane/2-(3-methoxy-4-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 4-(1H-benzo[d]imidazol-1-ylamino)-2-bromobenzonitrile [Example 2 step B]. The title compound was obtained as a white solid (34 mg, 23%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 10.42 (s, 1H), 8.46 (s, 1H), 8.24 (s, 2H), 7.78-7.77 (d, J=8.5 Hz, 2H), 7.46-7.45 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 7.32-7.28 (m, 4H), 6.58 (s, 1H), 6.52-6.51 (d, J=9.5 Hz, 1H), 2.43 (s, 3H); MS (ESI) m/z: 452 [M+H].sup.+.

Example 21

5-((1H-Benzo[d]imidazol-1-yl)amino)-2-cyano-4-(methylthio)-[1,1-biphenyl]-3-yl sulfamate

[0248] Compound of Example 21 was prepared in the same manner as described for compound of Example 19 starting from 5-((1H-benzo[d]imidazol-1-yl)amino)-3-hydroxy-4-(methylthio)-[1,1-biphenyl]-2-carbonitrile. The title compound was obtained as white solid (25 mg). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 10.41 (s, 1H), 8.46 (s, 1H), 8.20 (s, 2H), 7.75-7.74 (d, J=8.7 Hz, 2H), 7.48 (s, 1H), 7.43-7.42 (m, 2H), 7.34-7.28 (m, 3H), 6.68 (s, 1H), 6.42-6.40 (d, J=8.2 Hz, 1H), 2.48 (s, 3H); MS (ESI) m/z: 452 [M+H].sup.+.

Example 22

4-(6-(1H-Benzo[d]imidazol-1-ylamino)-3-cyanopyridin-2-yl)phenyl sulfamate

Step A. 2-(4-Methoxyphenyl)nicotinonitrile

[0249] The procedure described in Example 1 step C was repeated using 2-chloronicotinonitrile (5 g) and 4-methoxyphenylboronic acid to obtain the title compound as a white solid (7.5 g, 95%). MS (ESI) m/z: 211 [M+H].sup.+.

Step B. 3-Cyano-2-(4-methoxyphenyl)pyridine 1-oxide

[0250] To a solution of 2-(4-methoxyphenyl)nicotinonitrile (8 g, 40 mmol) in CH.sub.2Cl.sub.2 (180 mL), at 0 C., was added m-CPBA (13.7 g, 80 mmol). The mixture was stirred at 25 C. for 20 hours before addition of solid Na.sub.2S.sub.2O.sub.3 and further stirring for 10 minutes. The reaction mixture was quenched with water and extracted with EtOAc (3200 mL). The organic solutions were collected and washed with a saturated aqueous solution of Na.sub.2CO.sub.3 then brine. After drying over MgSO.sub.4, filtration and evaporation under reduced pressure, the residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (50:1-10:1) to afford 3-cyano-2-(4-methoxyphenyl)pyridine 1-oxide as a white solid (7.5 g, 83%). MS (ESI) m/z: 227 [M+H].sup.+.

Step C. 6-Chloro-2-(4-methoxyphenyl)nicotinonitrile

[0251] A solution of 3-cyano-2-(4-methoxyphenyl)pyridine 1-oxide (7.5 g, 35.4 mmol) in POCl.sub.3 (100 mL) was heated at 100 C. for 20 hours. Ice-water was slowly added to the reaction mixture followed by dry Na.sub.2CO.sub.3 until pH 8. After extraction with EtOAc (3200 mL), the organic solutions were combined, dried over Na.sub.2SO.sub.4, filtered and were evaporated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (70:1-20:1) to afford 6-chloro-2-(4-methoxyphenyl)nicotinonitrile as a white solid (2.1 g, 24.4%). MS (ESI) m/z: 345 [M+H].sup.+.

Step D. 6-(1H-Benzo[d]imidazol-1-ylamino)-2-(4-methoxyphenyl)nicotinonitrile

[0252] The procedure described in Example 2 Step B was repeated using 6-chloro-2-(4-methoxyphenyl)nicotinonitrile (750 mg) and 1H-benzo[d]imidazol-1-amine to afford the title compound as a white solid (780 mg, 75%). MS (ESI) m/z: 342 [M+H].sup.+.

Step E. 4-(6-(1H-Benzo[d]imidazol-1-ylamino)-3-cyanopyridin-2-yl)phenyl sulfamate

[0253] The procedures described in Example 2 steps D and E were repeated using 6-(1H-benzo[d]imidazol-1-ylamino)-2-(4-methoxyphenyl)nicotinonitrile (190 mg) to afford the title compound as white solid (26 mg, 6%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 11.10 (brs, 1H), 8.45 (s, 1H), 8.13-8.10 (m, 3H), 7.75-7.73 (m, 3H), 7.37-7.35 (m, 3H), 7.29-7.28 (m, 2H), 6.56 (brs, 1H); MS (ESI) m/z: 407 [M+H].sup.+.

Example 23

4-(6-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-3-cyanopyridin-2-yl)phenyl sulfamate

[0254] Compound of Example 23 was prepared in the same manner as described for compound of Example 16 starting from 6-((1H-benzo[d]imidazol-1-yl)(methyl)amino)-2-(4-methoxyphenyl)nicotinonitrile. The title compound was obtained as a white solid (110 mg, 32%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.61 (s, 1H), 8.17 (s, 2H), 8.06 (d, J=8.5 Hz, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.81-7.80 (m, 1H), 7.46-7.41 (m, 3H), 7.34-7.32 (m, 2H), 6.18 (brs, 1H), 3.74 (s, 3H); MS (ESI) m/z: 421 [M+H].sup.+.

Example 24

2-Cyano-5-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)biphenyl-4-yl sulfamate

Step A. 5,6-Difluoro-1H-benzo[d]imidazole

[0255] A solution of 4,5-difluorobenzene-1,2-diamine (1.5 g, 10 mmol) in formic acid (20 mL) was heated at 80 C. for 12 hours. The reaction mixture was cooled to 25 C. and concentrated under reduced pressure. The residue was recrystallized form Petroleum ether:EtOAc (15:1) to afford 5,6-difluoro-1 H-benzo[d]imidazole as a yellow solid (1.4 g, 88%). MS (ESI) m/z: 155 [M+H].sup.+.

Step B. 2-Bromo-4-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile

[0256] A solution of 5,6-difluoro-1H-benzo[d]imidazole (1.4 g, 9 mmol), 2-bromo-4-(bromomethyl) benzonitrile (2.5 g, 9 mmol) [see Example 1 Step A] and K.sub.2CO.sub.3 (3.8 g, 27 mmol) in CH.sub.3CN (50 mL) was heated at 25 C. for 12 hours. The reaction mixture was cooled to 25 C., filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum ether:EtOAc (30:13:1) as eluting solvents to afford 2-bromo-4-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile as a yellow solid (1.3 g, 39%). MS (ESI) m/z: 348 [M+H].sup.+.

Step C. 2-Cyano-5-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)biphenyl-4-yl sulfamate

[0257] The procedures described in Example 1 steps C, D and E were repeated using 2-bromo-4-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile to afford the title compound as yellow solid (38 mg, 27%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.56 (s, 1H), 8.15 (brs, 2H), 7.95 (d, J=7.5 Hz, 1H), 7.83 (dd, J.sub.1=2 Hz, J.sub.2=10.5 Hz, 1H), 7.75 (d, J=10.5 Hz, 1H), 7.65 (d, J=6.5 Hz, 2H), 7.64 (s, 1H), 7.46 (s, 1H), 7.45 (d, J=6.5 Hz, 2H), 5.63 (s, 2H). MS (ESI) m/z: 441 [M+H].sup.+.

Example 25

4-(2-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-5-cyanopyrimidin-4-yl)phenyl sulfamate

Step A. 2-(3H-Imidazo[4,5-b]pyridin-3-yl)acetonitrile

[0258] A mixture of 1H-benzo[d]imidazole (3.57 g, 30 mmol), ClCH.sub.2CN (2.7 g, 36 mmol), K.sub.2CO.sub.3 (8.28 g, 60 mmol) and KI (0.99 g, 6 mmol) in MeCN (50 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatograph using CH.sub.2Cl.sub.2:MeOH (40:1) as eluting solvents to afford 2-(3H-imidazo[4,5-b]pyridin-3-yl)acetonitrile as a yellow solid (2.0 g, 40%). MS (ESI) m/z: 159 [M+H].sup.+.

Step B. 2-(3H-Imidazo[4,5-b]pyridin-3-yl)acetimidamide

[0259] A mixture of 2-(3H-imidazo[4,5-b]pyridin-3-yl)acetonitrile (1.0 g, 6.33 mmol) and MeONa (0.034 g, 0.64 mmol) in THF (6 mL) and MeOH (15 mL) was heated at 45 C. overnight. After the reaction mixture was cooled, NH.sub.4Cl (0.68 g, 12.74 mmol) and MeOH (5 mL) were added. The mixture was stirred at 80 C. for 4 hours, quenched by H.sub.2O (5 mL), concentrated under reduced pressure, and recrystallized by H.sub.2O and EtOH to afford 2-(3H-imidazo[4,5-b]pyridin-3-yl)acetimidamide as a white solid (900 mg, 81%). MS (ESI) m/z: 176 [M+H].sup.+.

Step C. 2-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile

[0260] A mixture of 3-(dimethylamino)-2-(4-methoxybenzoyl)acrylonitrile (690 mg, 3 mmol), 2-(3H-imidazo[4,5-b]pyridin-3-yl)acetimidamide (525 mg, 3 mmol) [Example 9 Step C], and DIPEA (1161 mg, 9 mmol) in 2-pentanol (20 mL) was heated at 130 C. for 3 hours. The reaction mixture was cooled to 25 C., concentrated under reduced pressure and purified by silica gel chromatography using CH.sub.2Cl.sub.2:MeOH (80:1) as eluting solvents to afford 2-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile as a yellow solid (600 mg, 58%). MS (ESI) m/z: 343 [M+H].sup.+.

Step D. 4-(2-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-5-cyanopyrimidin-4-yl)phenyl sulfamate

[0261] The procedures described in Example 2 steps D and E were repeated using 2-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile (150 mg) to afford the title compound as a white solid (60 mg, 32%). .sup.1HNMR (500 MHz, DMSO-d.sub.6) (ppm) 9.31 (s, 1H), 8.62 (d, J=6 Hz, 1H), 8.31-8.30 (m, 1H), 8.21 (s, 2H), 8.15-8.13 (m, 1H), 7.98-7.96 (m, 2H), 7.50-7.46 (m, 2H), 7.31-7.29 (m, 1H), 5.93 (s, 2H); MS (ESI) m/z: 408 [M+H].sup.+

Example 26

4-(2-(1H-Benzo[d]imidazol-1-ylamino)-5-cyanopyridin-4-yl)phenyl sulfamate

Step A. 4-Chloro-5-iodopyridin-2-amine

[0262] A mixture of 4-chloropyridin-2-amine (2 g, 15.6 mmol) and N-iodosuccinimide (4.2 g, 18.7 mmol) in DMF (20 mL) was heated at 40 C. overnight. The reaction mixture was diluted by H.sub.2O (80 mL), extracted by EtOAc (40 mL*3). The combined organic solutions were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (4:1) as eluting solvents to afford 4-chloro-5-iodopyridin-2-amine as a red solid (2.8 g, 70%). MS (ESI) m/z: 255 [M+H].sup.+.

Step B. 2-(3H-Imidazo[4,5-b]pyridin-3-yl)acetimidamide

[0263] A mixture of 4-chloro-5-iodopyridin-2-amine (2.8 g, 11 mmol), Pd(PPh.sub.3).sub.4 (1.9 g, 1.65 mmol), and Zn(CN).sub.2 (0.7 g, 6.05 mmol) in NMP (30 mL) was heated at 130 C. for 5 hours. The reaction mixture was cooled to 23 C., diluted by H.sub.2O (200 mL) and filtered. The solid was purified by silica gel chromatography using Petroleum Ether:EtOAc (3:1) as eluting solvents to afford 2-(3H-imidazo[4,5-b]pyridin-3-yl)acetimidamide as a yellow solid (1.18 g, 70%). MS (ESI) m/z: 154 [M+H].sup.+.

Step C. 6-Amino-4-(4-methoxyphenyl)nicotinonitrile

[0264] A mixture of 2-(3H-imidazo[4,5-b]pyridin-3-yl)acetimidamide (1.18 g, 7.7 mmol), 4-methoxyphenylboronic acid (1.28 g, 8.4 mmol), Pd(OAc).sub.2 (0.093 g, 0.385 mmol), X-Phos (0.366 g, 0.77 mmol), and K.sub.3PO.sub.4 (4.89 g, 23.1 mmol) in toluene (40 mL) was heated at 85 C. overnight. The reaction mixture was cooled to 23 C., concentrated under reduced pressure and the residue purified by silica gel chromatography using Petroleum Ether:EtOAc (3:1) as eluting solvents to afford 6-amino-4-(4-methoxyphenyl)nicotinonitrile as a yellow solid (800 mg, 45%). MS (ESI) m/z: 226 [M+H].sup.+.

Step D. 6-Fluoro-4-(4-methoxyphenyl)nicotinonitrile

[0265] To a mixture of pyridine/HF (10 mL) in pyridine (10 mL) in an ice-bath was added 6-amino-4-(4-methoxyphenyl)nicotinonitrile (800 mg, 3.55 mmol). The mixture was stirred at 23 C. for 0.5 hour. After cooling down to 20 C., NaNO.sub.2 (367 mg, 5.32 mmol) was added and stirred at room temperature for 2 hours. After quenching by addition of a saturated aqueous solution of K.sub.2CO.sub.3 and extraction by EtOAc (20 mL*3), the combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (70:1) as eluting solvents to afford 6-fluoro-4-4-methoxyphenyl)nicotinonitrile as a white solid (400 mg, 49%). MS (ESI) m/z: 229 [M+H].sup.+.

Step E. 6-(1H-Benzo[d]imidazol-1-ylamino)-4-(4-methoxyphenyl)nicotinonitrile

[0266] A mixture of 6-fluoro-4-(4-methoxyphenyl)nicotinonitrile (400 mg, 1.75 mmol), Cs.sub.2CO.sub.3 (1137 mg, 3.5 mmol), and 1H-benzo[d]imidazol-1-amine (279 mg, 2.1 mmol) in DMF (10 mL) was stirred at 70 C. overnight. After cooling at 23 C., the reaction mixture was then quenched by H.sub.2O (80 mL) and extracted by EtOAc (30 mL*3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using CH.sub.2Cl.sub.2:MeOH (100:1) as eluting solvents to afford 6-(1H-benzo[d]imidazol-1-ylamino)-4-(4-methoxyphenyl)nicotinonitrile as a yellow solid (300 mg, 52%). MS (ESI) m/z: 342 [M+H].sup.+.

Step F. 4-(2-(1H-Benzo[d]imidazol-1-ylamino)-5-cyanopyridin-4-yl)phenyl sulfamate

[0267] The procedures described in Example 2 steps D and E were repeated using 6-(1H-benzo[d]imidazol-1-ylamino)-4-(4-methoxyphenyl)nicotinonitrile to afford the title compound as a white solid (95 mg, 42%). .sup.1HNMR (500 MHz, DMSO-d.sub.6) (ppm) 8.63 (s, 1H), 8.42 (s, 1H), 8.25 (br, 2H), 7.75-7.73 (m, 2H), 7.68 (d, J=8.5 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H), 7.36-7.34 (m, 1H), 7.30-7.26 (m, 2H), 6.65 (br, 1H); MS (ESI) m/z: 407 [M+H].sup.+.

Example 27

5-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-2-cyano-3-(methylthio)-[1,1-biphenyl]-4-yl sulfamate

Step A. 5-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-4-methoxy-3-(methylthio)-[1,1-biphenyl]-2-carbonitrile and 5-((1H-benzo[d]imidazol-1-yl)(methyl)amino)-3-methoxy-4-(methylthio)-[1,1-biphenyl]-2-carbonitrile

[0268] To a mixture of 5-((1H-benzo[d]imidazol-1-yl)amino)-4-methoxy-3-(methylthio)-[1,1-biphenyl]-2-carbonitrile and 5-((1H-benzo[d]imidazol-1-yl)amino)-3-methoxy-4-(methylthio)-[1,1-biphenyl]-2-carbonitrile (860 mg, 2.22 mmol) [see Example 20] in THF (40 mL) was added NaH (501 mg, 3.34 mmol) at 0 C. The mixture was stirred at 0 C. for one hour before a dropwise addition of CH.sub.31 (474 mg, 3.34 mmol). After two more hours at 0 C., the reaction mixture was evaporated under reduced pressure. The residue was purified by silica gel column using Petroleum Ether: EtOAc (1:1) as solvents to afford 5-((1H-benzo[d]imidazol-1-yl)(methyl)amino)-4-methoxy-3-(methylthio)biphenyl-2-carbonitrile and 5-((1H-benzo[d]imidazol-1-yl)(methyl)amino)-3-methoxy-4-(methylthio)biphenyl-2-carbonitrile as a yellow solid (806 mg, 90%). MS (ESI) m/z: 401 [M+H].sup.+.

Step B. 5-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-4-hydroxy-3-(methylthio)-[1,1-biphenyl]-2-carbonitrile and 5-((1H-benzo[d]imidazol-1-yl)(methyl)amino)-3-hydroxy-4-(methylthio)-[1,1-biphenyl]-2-carbonitrile

[0269] The procedure describe in Example 18 step D was repeated using a mixture of 5-((1H-benzo[d]imidazol-1-yl)(methyl)amino)-4-methoxy-3-(methylthio)biphenyl-2-carbonitrile and 5-((1H-benzo[d] imidazol-1-yl)(methyl)amino)-3-methoxy-4-(methylthio)biphenyl-2-carbonitrile to afford the title compounds as 5-((1H-benzo[d]imidazol-1-yl)(methyl)amino)-4-hydroxy-3-(methylthio)-[1,1-biphenyl]-2-carbonitrile as a white solid (200 mg, 25.9%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 10.22 (s, 1H), 8.57 (s, 1H), 7.79-7.77 (d, J=8.9 Hz, 1H), 7.72-7.70 (d, J=8.7 Hz, 1H), 7.37-7.35 (m, 1H), 7.31-7.30 (m, 2H), 7.13-7.11 (m, 2H), 6.88-6.86 (d, J=8.1 Hz, 1H), 6.64 (s, 1H), 6.43-6.41 (d, J=8.7 Hz, 1H), 3.64 (s, 3H), 2.33 (s, 3H); MS (ESI) m/z: 387 [M+H]+ and 5-((1H-benzo[d]imidazol-1-yl)(methyl)amino)-3-hydroxy-4-(methylthio)-[1,1-biphenyl]-2-carbonitrile as a white solid (160 mg, 20.7%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 10.12 (s, 1H), 8.58 (s, 1H), 7.79-7.78 (m, 1H), 7.75-7.73 (d, J=8.7 Hz, 1H), 7.39-7.37 (m, 1H), 7.32-7.29 (m, 2H), 7.18-7.16 (d, J=7.9 Hz, 1H), 6.91-6.89 (m, 2H) 6.58 (s, 1H), 6.51-6.49 (d, J=8.7 Hz, 1H), 3.63 (s, 3H), 2.39 (s, 3H); MS (ESI) m/z: 387 [M+H].sup.+.

Step C. 5-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-2-cyano-3-(methylthio)-[1,1-biphenyl]-4-yl sulfamate

[0270] The procedure described in Example 18 step E was repeated using 5-((1H-benzo[d]imidazol-1-yl)(methyl)amino)-4-hydroxy-3-(methylthio)-[1,1-biphenyl]-2-carbonitrile to afford the title compound as a white solid (90 mg, 41%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.58 (s, 1H), 8.26 (s, 2H), 7.80-7.77 (m, 2H), 7.48-7.46 (d, J=8.3 Hz, 1H), 7.37-7.36 (m, 2H), 7.34-7.31 (m, 3H), 6.74 (s, 1H), 6.48-6.46 (d, J=8.7, 1H), 3.66 (s, 3H), 2.44 (s, 3H); MS (ESI) m/z: 466 [M+H].sup.+.

Example 28

5-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-2-cyano-4-(methylthio)-[1,1-biphenyl]-3-yl sulfamate

[0271] Compound of Example 28 was prepared in the same manner as described for compound of Example 27 starting from 5-((1H-benzo[d]imidazol-1-yl)(methyl)amino)-3-hydroxy-4-(methylthio)-[1,1-biphenyl]-2-carbonitrile. The title compound was obtained as a white solid (80 mg, 47%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.58 (s, 1H), 8.22 (s, 2H), 7.80-7.78 (m, 1H), 7.76-7.74 (d, J=8.8 Hz, 1H), 7.52 (s, 1H), 7.46 (s, 2H), 7.38-7.36 (m, 1H), 7.32-7.30 (m, 2H), 6.84 (s, 1H), 6.39-6.37 (d, J=8.8 Hz, 1H), 3.64 (s, 3H), 2.49 (s, 3H); MS (ESI) m/z: 466 [M+H].sup.+.

Example 29

4-(2-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-5-cyanopyridin-4-yl)phenyl sulfamate

[0272] Compound of Example 29 was prepared in the same manner as described for compound of Example 16 using 6-(1H-benzo[d]imidazol-1-ylamino)-4-(4-methoxyphenyl)nicotinonitrile to afford the title compound as a white solid (90 mg, 56%). .sup.1HNMR (500 MHz, DMSO-d.sub.6) (ppm) 8.77 (s, 1H), 8.57 (s, 1H), 8.10 (br, 2H), 7.78-7.76 (m, 1H), 7.69 (d, J=8.5 Hz, 2H), 7.41-7.39 (m, 3H), 7.31-7.29 (m, 2H), 6.35 (s, 1H), 3.73 (s, 3H); MS (ESI) m/z: 421 [M+H].sup.+.

Example 30

6-(5-((1H-Benzo[d]imidazol-1-yl)methyl)-2-cyanophenyl)pyridin-3-yl sulfamate

Step A. 2-Bromo-5-((2-(trimethylsilyl)ethoxy)methoxy)pyridine

[0273] To a suspension of 6-bromopyridin-3-ol (8.63 g, 49.6 mmol) in CH.sub.2Cl.sub.2 (130 mL) was added diisopropylethylamine (6.4 g, 49.6 mmol). A clear solution was thus obtained and 2-(trimethylsilyl)ethoxy methyl chloride (8.3 g, 49.6 mmol) was added. After overnight stirring, the mixture was diluted with CH.sub.2Cl.sub.2 (250 mL) and washed with a saturated aqueous solution of NaHCO.sub.3 (150 mL) and brine (150 mL). The organic layer was dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (100:1-80:1) as eluting solvents to afford 2-bromo-5-((2-(trimethylsilyl)ethoxy)methoxy)pyridine as a pale yellow oil (13.32 g, 88%). MS (ESI) m/z: 304 [M+H].sup.+.

Step B. 2-(Tributylstannyl)-5-((2-(trimethylsilyl)ethoxy)methoxy)pyridine

[0274] A mixture of 2-bromo-5-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (7.74 g, 25.4 mmol), bis(tributyltin) (22.2 g, 38.3 mmol), and Pd(PPh.sub.3).sub.4 (2.93 g, 2.54 mmol) in toluene (100 mL) was purged with nitrogen and heated at 120 C. overnight. The reaction mixture was cooled to 23 C. and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (200:1) as eluting solvents to afford 2-(tributylstannyl)-5-((2-(trimethylsilyl)ethoxy)methoxy)pyridine as a yellow oil (1.33 g, 10%). MS (ESI) m/z: 516 [M+H].sup.+.

Step C. 4-((1H-Benzo[d]imidazol-1-yl)methyl)-2-(5-((2-(trimethylsilyl)ethoxy)methoxy)pyridin-2-yl)benzonitrile

[0275] A mixture of 2-(tributylstannyl)-5-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (1.33 g, 2.59 mmol), 4-((1H-benzo[d]imidazol-1-yl)methyl)-2-bromobenzonitrile (888 mg, 2.84 mmol), and Pd(PPh.sub.3).sub.4 (324 mg, 0.28 mmol) in toluene (20 mL) was purged with nitrogen and heated at 120 C. for 48 hours. The reaction mixture was cooled to 23 C. and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (4:1-1:1) as eluting solvents to afford 4-((1H-benzo[d]imidazol-1-yl)methyl)-2-(5-((2-(trimethylsilyl)ethoxy)methoxy)pyridin-2-yl)benzonitrile (830 mg, 70%). MS (ESI) m/z: 457 [M+H].sup.+.

Step D. 4-((1H-Benzo[d]imidazol-1-yl)methyl)-2-(5-hydroxypyridin-2-yl)benzonitrile

[0276] A mixture of 4-((1H-benzo[d]imidazol-1-yl)methyl)-2-(5-((2-(trimethylsilyl)ethoxy)methoxy)pyridin-2-yl)benzonitrile (680 mg, 1.49 mmol) and tetrabutylammonium fluoride (1.95 g, 7.45 mmol) in tetrahydrofuran (20 mL) was stirred at ambient temperature for 48 hours. The reaction mixture was quenched by adding water (20 mL) and extracted with CH.sub.2Cl.sub.2 (330 mL). The organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using CH.sub.2Cl.sub.2:CH.sub.3OH (15:1) as eluting solvents to afford 4-((1H-benzo[d]imidazol-1-yl)methyl)-2-(5-hydroxypyridin-2-yl)benzonitrile as a solid (140 mg, 29%). MS (ESI) m/z: 327 [M+H].sup.+.

Step E. 6-(5-((1H-Benzo[d]imidazol-1-yl)methyl)-2-cyanophenyl)pyridin-3-yl sulfamate

[0277] The procedure described in Example 1 Step D was repeated using 4-((1H-benzo[d]imidazol-1-yl)methyl)-2-(5-hydroxypyridin-2-yl)benzonitrile (140 mg, 0.43 mmol) and sulfamoyl chloride (495 mg, 4.3 mmol) to afford the title compound as a white solid (34 mg, 20%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.65 (d, 1H), 8.51 (s, 1H), 8.32 (s, 2H), 7.92-7.98 (m, 3H), 7.86 (d, 1H), 7.68 (d, 1H), 7.56 (d, 1H), 7.49 (q, 1H), 7.21-7.23 (m, 2H), 5.70 (s, 2H); MS (ESI) m/z: 406 [M+H].sup.+.

Example 31

4-(5-((1H-Benzo[d]imidazol-1-yl)methyl)-2-cyanopyridin-3-yl)phenyl sulfamate

Step A. (5,6-Dichloropyridin-3-yl)methanol

[0278] To a solution of ethyl-5,6-dichloronicotinate (22 g, 100 mmol) in MeOH (220 mL) at 0 C. was added sodium borohydride (18.9 g, 500 mmol) in several small portions. After stirring with at 23 C. for 5 hours, the reaction was quenched by addition of water (100 mL). The mixture was extracted with CH.sub.2Cl.sub.2 (3200 mL). The extracts were combined, dried over MgSO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (10:1-6:1) as eluting solvents to afford (5,6-dichloropyridin-3-yl)methanol as a clear oil (9.7 g, 55%). MS (ESI) m/z: 178 [M+H].sup.+.

Step B. 3-Chloro-5-(hydroxymethyl)picolinonitrile

[0279] A mixture of (5,6-dichloropyridin-3-yl)methanol (9.7 g, 54.5 mmol), zinc cyanide (3.52 mg, 30 mmol), and Pd(PPh.sub.3).sub.4 (6.3 g, 8.18 mmol) in NMP (100 mL) was purged with nitrogen and heated at 100 C. for 48 hours. After cooling to 23 C., water (100 mL) was added. The mixture was extracted with EtOAc (3150 mL) and the extracts were combined, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (6:12:1) as eluting solvents to afford 3-chloro-5-(hydroxymethyl)picolinonitrile as a white solid (1.96 g, 21%). MS (ESI) m/z: 169 [M+H].sup.+.

Step C. 5-(Bromomethyl)-3-chloropicolinonitrile

[0280] To a solution of 3-chloro-5-(hydroxymethyl)picolinonitrile (1.96 g, 11.63 mmol) in THF (35 mL) was added phosphorus tribromide (4.10 g, 15.11 mmol) in a dropwise manner. After 2 hours stirring at 23 C., the reaction mixture was cooled to 0 C. before the slow addition of a saturated aqueous solution of NaHCO.sub.3 (20 mL). This mixture was extracted with CH.sub.2Cl.sub.2 (340 mL), the combined organic solutions were dried over MgSO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (15:1-10:1) as eluting solvents to afford 5-(bromomethyl)-3-chloropicolinonitrile as a oil (2.01 g, 75%). MS (ESI) m/z: 231 [M+H].sup.+.

Step D. 5-((1H-Benzo[d]imidazol-1-yl)methyl)-3-chloropicolinonitrile

[0281] To a solution of 5-(bromomethyl)-3-chloropicolinonitrile (2.01 g, 8.68 mmol) in CH.sub.3CN (20 mL) was added benzimidazole (1.13 g, 9.55 mmol) and K.sub.2CO.sub.3 (2.40, 17.37 mmol). After stirring at 40 C. for 2 hours, the mixture was cooled and filtered. The filtrate was concentrated under reduced pressure.

[0282] The residue was purified by silica gel chromatography to afford 5-((1H-benzo[d]imidazol-1-yl)methyl)-3-chloropicolinonitrile as a white solid (1.2 g, 51%). MS (ESI) m/z: 269 [M+H].sup.+.

Step E. 5-((1H-Benzo[d]imidazol-1-yl)methyl)-3-(4-(benzyloxy)phenyl)picolinonitrile

[0283] The procedure described in Example 1 step C was repeated using 5-((1H-benzo[d]imidazol-1-yl)methyl)-3-chloropicolinonitrile (402 mg, 1.50 mmol) and 4-(benzyloxy)phenylboronic acid (513 mg, 2.25 mmol), the title compound was obtained as a solid (680 mg, 80%). MS (ESI) m/z: 417 [M+H].sup.+.

Step F. 5-((1H-Benzo[d]imidazol-1-yl)methyl)-3-(4-hydroxyphenyl)picolinonitrile

[0284] To a solution of Pd(OAc).sub.2 (75 mg, 0.32 mmol) and triethylsilane (4.5 mL) in CH.sub.2Cl.sub.2 (10 mL) was added triethylamine (2.2 mL). After the mixture was stirred at ambient temperature for 15 minutes, a solution of 5-((1H-benzo[d]imidazol-1-yl)methyl)-3-(4-(benzyloxy)phenyl)picolinonitrile (600 mg, 1.28 mmol) in CH.sub.2Cl.sub.2 (15 mL) was added. The reaction mixture was stirred for 4 hours, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford 5-((1H-benzo[d]imidazol-1-yl)methyl)-3-(4-hydroxyphenyl)-picolinonitrile as a solid (115 mg, 22%). MS (ESI) m/z: 327 [M+H].sup.+.

Step G. 4-(5-((1H-Benzo[d]imidazol-1-yl)methyl)-2-cyanopyridin-3-yl)phenyl sulfamate

[0285] The procedure described in Example 1 step E was repeated using 5-((1H-benzo[d]imidazol-1-yl)methyl)-3-(4-hydroxyphenyl)picolinonitrile (115 mg, 0.35 mmol) and sulfamoyl chloride (407 mg, 3.5 mmol), the title compound was obtained as a white solid (81 mg, 57%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.80 (d, 1H), 8.50 (s, 1H), 8.17 (s, 2H), 8.06 (d, 1H), 7.64-7.73 (m, 4H), 7.45-7.47 (m, 2H), 7.20-7.26 (m, 2H), 5.72 (s, 2H); MS (ESI) m/z: 406 [M+H].sup.+.

Example 32

4-(6-(1H-Benzo[d]imidazol-1-ylamino)-3-cyanopyrazin-2-yl)phenyl sulfamate

Step A. 6-Chloro-5-iodopyrazin-2-amine

[0286] To a solution of 6-chloropyrazin-2-amine (10 g, 77.2 mmol) in DMSO (100 mL) was added NIS (17.4 g, 77.2 mmol) and the solution was stirred at 25 C. overnight. After the mixture was poured into water and extracted with EtOAc, the organic solutions were collected, washed with brine, dried over NaSO.sub.4 and filtered. The filtrate was evaporated under reduced pressure and the residue purified by silica gel chromatograph using Petroleum Ether:EtOAc 1:4 as eluting solvents to afford 6-chloro-5-iodopyrazin-2-amine as a yellow solid (17.2 g, 88%). MS (ESI) m/z: 255 [M+H].sup.+.

Step B. 5-Amino-3-chloropyrazine-2-carbonitrile

[0287] A mixture of 6-chloro-5-iodopyrazin-2-amine (17.2 g, 67.7 mmol), Zn(CN).sub.2 (4.35 g, 37.2 mmol) and Pd(PPh.sub.3).sub.4 (3.9 g, 3.4 mmol) in NMP was heated at 100 C. for 14 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography using Petroleum Ether:EtOAc 1:4 as eluting solvents to afford 5-amino-3-chloropyrazine-2-carbonitrile as a yellow solid (9.4 g, 90%). MS (ESI) m/z: 155 [M+H].sup.+.

Step C. 5-Amino-3-(4-(benzyloxy)phenyl)pyrazine-2-carbonitrile

[0288] The procedure described in Example 1 step C was repeated using 5-amino-3-chloropyrazine-2-carbonitrile (6 g, 39 mmol) and 4-(benzyloxy)phenylboronic acid (9.3 g, 41 mmol) to afford the title compound as a yellow solid (10 g, 85%). MS (ESI) m/z: 303 [M+H].sup.+.

Step D. 3-(4-(Benzyloxy)phenyl)-5-bromopyrazine-2-carbonitrile

[0289] A mixture of CuBr.sub.2 (8 g, 35.7 mmol), t-butylnitrite (4.6 g, 45 mmol) in CH.sub.3CN (100 mL) was heated at 60 C. for 5 minutes before addition of 5-amino-3-(4-(benzyloxy)phenyl)pyrazine-2-carbonitrile (9 g, 29.7 mmol). The reaction mixture was stirred for another 10 minutes before pouring into a 2.0 N aqueous solution of HCl (100 mL). After extraction with EtOAc and washing with a 2.0 N aqueous solution of HCl, the organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 3-(4-(benzyloxy)phenyl)-5-bromopyrazine-2-carbonitrile as a yellow solid (5.8 g, 45%). MS (ESI) m/z: 367 [M+H].sup.+.

Step E. 5-(1H-Benzo[d]imidazol-1-ylamino)-3-(4-(benzyloxy)phenyl)pyrazine-2-carbonitrile

[0290] The procedure described in Example 2 step B was repeated using 3-(4-(benzyloxy)phenyl)-5-bromopyrazine-2-carbonitrile (2.5 g, 6.8 mmol) to afford the title compound as a yellow solid (1 g, 35%). MS (ESI) m/z: 419 [M+H].sup.+.

Step F. 5-(1H-Benzo[d]imidazol-1-ylamino)-3-(4-hydroxyphenyl)pyrazine-2-carbonitrile

[0291] A solution of 5-(1H-benzo[d]imidazol-1-ylamino)-3-(4-(benzyloxy)phenyl) pyrazine-2-carbonitrile (500 mg, 1.37 mmol) in CF.sub.3CO.sub.2H (10 mL) was heated at 90 C. for 10 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether:EtOAc 1:1 as eluting solvents to afford 5-(1H-benzo[d]imidazol-1-ylamino)-3-(4-hydroxyphenyl)pyrazine-2-carbonitrile as a white solid (150 mg, 38%). MS (ESI) m/z: 329 [M+H].sup.+.

Step G. 4-(6-(1H-Benzo[d]imidazol-1-ylamino)-3-cyanopyrazin-2-yl)phenyl sulfamate

[0292] The procedure described in Example 1 step E was repeated using 5-(1H-benzo[d]imidazol-1-ylamino)-3-(4-hydroxyphenyl)pyrazine-2-carbonitrile (150 mg, 0.46 mmol) to afford the title compound as a yellow solid (30 mg, 16%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 11.70 (s, 1H), 8.46 (s, 1H), 8.22 (br, 1H), 8.11 (s, 2H), 7.74 (d, J=7.2 Hz, 1H), 7.70 (m, 2H), 7.46 (d, J=5.6 Hz, 1H), 7.36 (d, J=8.2 Hz, 2H), 7.29 (m, 2H); MS (ESI) m/z: 408 [M+H].sup.+.

Example 33

6-(5-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-2-cyanophenyl)pyridin-3-yl sulfamate

Step A. 4-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-2-(5-((2-(trimethylsilyl)ethoxy) methoxy)pyridin-2-yl)benzonitrile

[0293] The procedure described in Example 30 step C was repeated using 2-(tributylstannyl)-5-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (800 mg, 1.52 mmol) and 4-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-bromobenzonitrile (400 mg, 1.38 mmol) [Example 12 step A] to afford the title compound as a brown solid (560 mg, 89%). MS (ESI) m/z: 458 [M+H].sup.+.

Step B. 4-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-2-(5-hydroxypyridin-2-yl)benzonitrile

[0294] To a solution of 4-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(5-((2-(trimethylsilyl)ethoxy) methoxy)pyridin-2-yl)benzonitrile (300 mg, 0.656 mmol) in CH.sub.2Cl.sub.2 (50 mL) at 0 C. was added CF.sub.3CO.sub.2H (0.5 mL). The mixture was stirred at room temperature for 4 hours. After evaporation under reduced pressure, the residue was purified by preparative HPLC to afford 4-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(5-hydroxypyridin-2-yl)benzonitrile as a white solid (97 mg, 45%). MS (ESI) m/z: 328 [M+H].sup.+.

Step C. 6-(5-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-2-cyanophenyl)pyridin-3-yl sulfamate

[0295] The procedure described in Example 1 step E was repeated using 4-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(5-hydroxypyridin-2-yl)benzonitrile (90 mg) and sulfamoyl chloride, the title compound was obtained as yellow solid (55 mg, 49%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.68 (s, 1H), 8.65 (d, J=2.5 Hz, 1H), 8.36 (d, J=5.0 Hz, 1H), 8.33 (s, 2H), 8.12 (d, J=8.0 Hz, 1H), 7.92-7.97 (m, 3H), 7.87 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 5.69 (s, 2H); MS (ESI) m/z: 407 [M+H].sup.+.

Example 34

4-(6-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-3-cyanopyrazin-2-yl)phenyl sulfamate

Step A. 5-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-3-(4-(benzyloxy)phenyl)pyrazine-2-carbonitrile

[0296] The procedure described in Example 5 step A was repeated using 5-(1H-benzo[d]imidazol-1-ylamino)-3-(4-(benzyloxy)phenyl)pyrazine-2-carbonitrile (2 g, 4.8 mmol) to afford the title compound as a yellow solid (1.86 g, 90%). MS (ESI) m/z: 433 [M+H].sup.+.

Step B. 5-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-3-(4-hydroxyphenyl)pyrazine-2-carbonitrile

[0297] The procedure described in Example 32 step F was repeated using 5-((1H-benzo[d]imidazol-1-yl)(methyl)amino)-3-(4-(benzyloxy)phenyl)pyrazine-2-carbonitrile (1.6 g, 3.68 mmol) to afford the title compound as a white solid (400 mg, 31.5%). MS (ESI) m/z: 343 [M+H].sup.+.

Step C. 4-(6-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-3-cyanopyrazin-2-yl)phenyl sulfamate

[0298] The procedure described in Example 1 step E was repeated using 5-((1H-benzo[d]imidazol-1-yl)(methyl)amino)-3-(4-hydroxyphenyl)pyrazine-2-carbonitrile (350 mg, 1.02 mmol) to afford the title compound as a white solid (67 mg, 15.6%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.62 (s, 1H), 8.18 (s, 2H), 7.93 (s, 2H), 8.38 (m, 1H), 7.52 (m, 1H), 7.46 (d, J=8.5 Hz, 2H), 7.35 (m, 2H), 3.77 (s, 3H); MS (ESI) m/z: 422 [M+H].sup.+.

Example 35

5-(3H-[1,2,3]Triazolo[4,5-b]pyridin-3-ylamino)-2-cyano-[1,1-biphenyl]-4-yl sulfamate

Step A. 2-Hydrazinyl-3-nitropyridine

[0299] To a solution of 2-chloro-3-nitropyridine (50 g, 316 mmol) in acetonitrile (500 mL) at 0 C. was added hydrazine hydrate (28 g, 474 mmol) and stirred at 20 C. for 20 hours. The reaction mixture was concentrated under reduced pressure to afford 2-hydrazinyl-3-nitropyridine as a yellow solid (48 g, 100%). MS (ESI) m/z: 155.1 [M+H].sup.+.

Step B. tert-Butyl 2-(3-nitropyridin-2-yl)hydrazinecarboxylate

[0300] To a solution of 2-hydrazinyl-3-nitropyridine (48 g, 316 mmol) and K.sub.2CO.sub.3 (129 g, 948 mmol) in 1,4-dioxane (500 ml) at 0 C. was added neat di-tert-butyl dicarbonate (71 g, 327 mmol) in a dropwise manner. The mixture was stirred at room temperature for 12 hours before filtration and concentration under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (5:1-3:1) as eluting solvents to afford tert-butyl 2-(3-nitropyridin-2-yl)hydrazinecarboxylate as a yellow solid (49 g, 50%). MS (ESI) m/z: 255.1 [M+H].sup.+.

Step C. tert-Butyl 2-(3-aminopyridin-2-yl)hydrazinecarboxylate

[0301] To a solution of tert-butyl 2-(3-nitropyridin-2-yl)hydrazinecarboxylate (49 g, 193 mmol) in MeOH (500 ml) was added 10% Pd/C (2 g). The mixture was stirred under hydrogen atmosphere at room temperature for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to afford tert-butyl 2-(3-aminopyridin-2-yl)hydrazinecarboxylate as a brown solid (40 g, 93%). MS (ESI) m/z: 225.2 [M+H].sup.+.

Step D. tert-Butyl 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ylcarbamate

[0302] To a solution of tert-butyl 2-(3-aminopyridin-2-yl)hydrazinecarboxylate (40 g, 179 mmol) and acetic acid (50 mL) in THF 400 (mL) at 0 C. was added neat tert-butyl nitrite (28 g, 269 mmol) dropwise. The reaction mixture was stirred at 20 C. for 8 hours and then quenched by addition of an aqueous solution of NaHCO.sub.3 (10%, 200 mL). After extraction with EtOAc (200 mL), the organic solution was dried over MgSO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (5:1-2:1) as eluting solvents to afford tert-butyl 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ylcarbamate as a brownish solid (30 g, 73%). MS (ESI) m/z: 236.1 [M+H].sup.+.

Step E. 3H-[1,2,3]Triazolo[4,5-b]pyridin-3-amine

[0303] To a solution of tert-butyl 3H-imidazo[4,5-b]pyridin-3-ylcarbamate (30 g, 128 mmol) in CH.sub.2Cl.sub.2 (300 ml) at 0 C. was added trifluoroacetic acid (60 mL) dropwise. The resulting mixture was stirred at 23 C. for 4 hours before concentration under reduced pressure. An aqueous solution of NaHCO.sub.3 (10%, 300 mL) was added to the residue which was extracted with EtOAc (300 mL). The extract was dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (3:1-0:1) as eluting solvents to afford 3H-[1,2,3]triazolo [4,5-b]pyridin-3-amine as a yellow solid (12 g, 70%). MS (ESI) m/z: 136.1 [M+H].sup.+.

Step F. 5-(3H-[1,2,3]Triazolo[4,5-b]pyridin-3-ylamino)-2-cyano-[1,1-biphenyl]-4-yl sulfamate

[0304] The procedures described in Example 2 steps B, C, D and were repeated using 3H-[1,2,3]triazolo [4,5-b]pyridin-3-amine and 2-bromo-4-fluorobenzonitrile to afford the title compound as a white solid (110 mg). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 11.21 (s, 1H), 8.80 (dd, J=1.0 Hz and 4.5 Hz, 1H), 8.71 (dd, J=1.5 Hz and 10.0 Hz, 1H), 8.11 (s, 2H), 7.76 (d, J=8.0 Hz, 1H), 7.62-7.60 (m, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 6.67 (d, J=2.0 Hz, 2H), 6.54 (dd, J=2.0 and 8.5 Hz, 2H); MS (ESI) m/z: 408.0 [M+H].sup.+.

Example 36

4-(2-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-5-cyanopyridin-4-yl)phenyl sulfamate

Step A. 4-Chloro-6-methylnicotinonitrile

[0305] A solution of 4-hydroxy-6-methylnicotinamide (15 g, 92.6 mmol) in POCl.sub.3 (50 mL) was heated at 110 C. for 12 hours. After evaporation of the excess of POCl.sub.3 under reduced pressure, the residue was poured into ice-water and its pH was adjusted to about 8 with a saturated aqueous solution of Na.sub.2CO.sub.3. The mixture was extracted with EtOAc (150 mL3). The combined organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using Petroleum Ether:EtOAc (100:1-10:1) as eluting solvents to afford 4-chloro-6-methylnicotinonitrile as a white solid (8.5 g, 61%). MS (ESI) m/z: 153 [M+H].sup.+.

Step B. 6-(Bromomethyl)-4-chloronicotinonitrile

[0306] To a solution of 4-chloro-6-methylnicotinonitrile (7.0 g, 46 mmol) in CCl.sub.4 (50 mL) was added NBS (9.0 g, 50.6 mmol) and benzoyl peroxide (5.5 g, 23 mmol). The mixture was heated at 110 C. for 12 hours before cooling down to 25 C. and filtration of the precipitate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (100:1) as eluting solvents to afford 6-(bromomethyl)-4-chloronicotinonitrile as a brown oil (4.0 g, 38%). MS (ESI) m/z: 231 [M+H].sup.+.

Step C. 6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-4-chloronicotinonitrile

[0307] The procedure described in Example 1 step B was repeated using 6-(bromomethyl)-4-chloronicotinonitrile (1.6 g, 4.8 mmol) and 3H-imidazo[4,5-b]pyridine (0.58 g, 4.8 mmol) to afford the title compound as yellow solid (160 mg, 13%). MS (ESI) m/z: 270 [M+H].sup.+.

Step D. 4-(2-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)-5-cyanopyridin-4-yl)phenyl sulfamate

[0308] The procedures described in Example 2 steps C, D and E were repeated using 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-4-chloronicotinonitrile to afford the title compound as a yellow solid (90 mg, 36%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 9.00 (s, 1H), 8.61 (s, 1H), 8.31 (d, J=5.0 Hz, 1H), 8.19 (s, 2H), 8.11 (d, J=7.0 Hz, 1H), 7.78 (d, J=8.5 Hz, 2H), 7.72 (s, 1H), 7.49 (d, J=8.5 Hz, 2H), 7.28 (t, J=8.0 Hz, 1H); 5.80 (s, 2H); MS (ESI) m/z: 407 [M+H].sup.+.

Example 37

6-(5-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-2-cyanophenyl)pyridin-3-yl sulfamate

Step A. 4-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-2-bromobenzonitrile

[0309] The procedure described in Example 5 step A was repeated using 4-((1H-benzo[d]imidazol-1-yl)(methyl)amino)-2-bromobenzonitrile (1.8 g, 5.75 mmol) and MeI (1.22 g, 8.62 mmol) to afford the title compound as a white solid (1.83 g, 97%). MS (ESI) m/z: 327 [M+H].sup.+.

Step B. 6-(5-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-2-cyanophenyl)pyridin-3-yl sulfamate

[0310] The procedures described in Example 33 steps A, B and C were repeated using 4-((1H-benzo[d]imidazol-1-yl)(methyl)amino)-2-bromobenzonitrile to afford the title compound as a brown solid (85 mg, 49%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.62 (t, 2H), 8.31 (s, 2H), 7.88-7.93 (m, 2H), 7.79-7.82 (m, 2H), 7.38 (q, 1H), 7.30-7.34 (m, 2H), 6.97 (d, 1H), 6.60 (q, 1H), 3.65 (s, 3H); MS (ESI) m/z: 421 [M+H].sup.+.

Example 38

4-(5-(1H-Benzo[d]imidazol-1-ylamino)-2-cyanopyridin-3-yl)phenyl sulfamate

Step A. 3-(4-(Benzyloxy)phenyl)-5-chloropyridin-2-amine

[0311] A mixture of 3-bromo-5-chloropyridin-2-amine (10.0 g, 48.2 mmol), 2-(4-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3-dioxaborolane (17.94 g, 57.8 mmol), Pd(PPh.sub.3).sub.4 (2.78 g, 2.41 mmol), and K.sub.2CO.sub.3 (13.32 g, 96.4 mmol) in toluene (80 mL), EtOH (20 mL), and H.sub.2O (10 mL) was purged with nitrogen and heated at 85 C. overnight. The reaction mixture was cooled to 25 C., diluted by EtOAc (200 mL), and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by crystallization in EtOAc to afford 3-(4-(benzyloxy)phenyl)-5-chloropyridin-2-amine as a white solid (12.71 g, 85%). MS (ESI) m/z: 311 [M+H].sup.+.

Step B. 3-(4-(Benzyloxy)phenyl)-5-chloro-2-fluoropyridine

[0312] To a solution of 3-(4-(benzyloxy)phenyl)-5-chloropyridin-2-amine (12.71 g, 40.9 mmol), Olah's reagent (100 mL) (J. Fluorine Chemistry 1986, 33, 377) at 20 C. was added NaNO.sub.2 (5.65 g, 81.8 mmol) in small portions. After the addition of NaNO.sub.2, the solution was allowed to warm to 23 C. slowly and stirred for 2 hours. The reaction mixture was neutralized to pH=7 by adding a saturated aqueous solution of NaHCO.sub.3 and extracted with EtOAc (3100 mL). The combined EtOAc layers were dried over Na.sub.2SO4, filtered, concentrated under reduced pressure and purified by silica gel chromatography using Petroleum Ether and EtOAc as eluting solvents to afford 3-(4-(benzyloxy)phenyl)-5-chloro-2-fluoropyridine as a white solid (12.24 g, 94%). MS (ESI) m/z: 314 [M+H].

Step C. 3-(4-(Benzyloxy)phenyl)-5-chloropicolinonitrile

[0313] A solution of 3-(4-(benzyloxy)phenyl)-5-chloro-2-fluoropyridine (12.24 g, 39.01 mmol), KCN (12.70 g, 195.06 mmol) in NMP (100 mL) was stirred at 115 C. overnight. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether and EtOAc as eluting solvents to afford 3-(4-(benzyloxy)phenyl)-5-chloropicolinonitrile as a white solid (5.10 g, 41%). MS (ESI) m/z: 321 [M+H].sup.+.

Step D. 5-(1H-Benzo[d]imidazol-1-ylamino)-3-(4-(benzyloxy)phenyl)picolinonitrile

[0314] The procedure described in Example 2 step B was repeated using 3-(4-(benzyloxy)phenyl)-5-chloropicolinonitrile (2.0 g, 6.24 mmol) to afford the title compound as a white solid (1.40 g, 54%). MS (ESI) m/z: 418 [M+H].sup.+.

Step E. 5-(1H-Benzo[d]imidazol-1-ylamino)-3-(4-hydroxyphenyl)picolinonitrile

[0315] A solution of 5-(1H-benzo[d]imidazol-1-ylamino)-3-(4-(benzyloxy)phenyl)picolinonitrile (500 mg, 1.2 mmol), 10% PdC (50 mg), pyridine (1 mL), and MeOH (10 mL) under hydrogen atmosphere was stirred at room temperature for 2 hours. The solution was filtered, the filtrate was concentrated under reduced pressure to afford 5-(1H-benzo[d]imidazol-1-ylamino)-3-(4-hydroxyphenyl)picolinonitrile as a white solid (360 mg, 92%), which was without further purification. MS (ESI) m/z: 328 [M+H].sup.+.

Step F. 4-(5-(1H-Benzo[d]imidazol-1-ylamino)-2-cyanopyridin-3-yl)phenyl sulfamate

[0316] The procedure described in Example 1 step E was repeated using 5-(1H-benzo[d]imidazol-1-ylamino)-3-(4-hydroxyphenyl)picolinonitrile (495 mg, 4.28 mmol), the title compound was obtained as a white solid (200 mg, 57%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 10.70 (s, 1H), 8.49 (s, 1H), 8.11 (s, 3H), 7.76 (d, J=9.0 Hz, 1H), 7.59 (d, J=9.0 Hz, 2H), 7.39 (m, 3H), 7.30 (m, 2H), 6.70 (s, 1H); MS (ESI) m/z: 407 [M+H].sup.+.

Example 39

4-(5-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-2-cyanopyridin-3-yl)phenyl sulfamate

Step A. 5-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-3-(4-(benzyloxy)phenyl)-picolinonitrile

[0317] The procedure described in Example 5 step A was repeated using 5-(1H-benzo[d]imidazol-1-ylamino)-3-(4-(benzyloxy)phenyl)picolinonitrile (550 mg, 1.32 mmol) [Example 38 step D] to afford the title compound as a yellow solid (568 mg, 100%). MS (ESI) m/z: 432 [M+H].sup.+.

Step B. 4-(5-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-2-cyanopyridin-3-yl)phenyl sulfamate

[0318] The procedures described in Example 38 steps E and F were repeated using 5-((1H-Benzo[d]imidazol-1-yl)(methyl)amino)-3-(4-(benzyloxy)phenyl)picolinonitrile to afford the title compound as a white solid (160 mg, 43%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.60 (s, 1H), 8.14 (s, 2H), 7.90 (d, J=2.5 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 2H), 7.43 (m, 3H), 7.32 (m, 2H), 7.06 (d, J=2.5 Hz, 1H), 3.68 (s, 3H); MS (ESI) m/z: 421 [M+H].sup.+.

Example 40

4-(6-(3H-Imidazo[4,5-b]pyridin-3-ylamino)-3-cyanopyrazin-2-yl)phenyl sulfamate

Step A. tert-Butyl 3H-imidazo[4,5-b]pyridin-3-ylcarbamate

[0319] A solution of tert-butyl 2-(3-aminopyridin-2-yl)hydrazinecarboxylate (40 g, 178 mmol) [Example 35 step C] in triethyl orthoformate (200 mL) was stirred at 130 C. for 3 hours. Then the reaction mixture was concentrated under reduced pressure and the residue purified by silica gel chromatography using Petroleum Ether:EtOAc (1:0-3:1) as eluting solvents to afford tert-butyl 3H-imidazo[4,5-b]pyridin-3-ylcarbamate as a white solid (30 g, 72%). MS (ESI) m/z: 235.1 [M+H].sup.+.

Step B. 3H-Imidazo[4,5-b]pyridin-3-amine

[0320] To a solution of tert-butyl 3H-imidazo[4,5-b]pyridin-3-ylcarbamate (30 g, 128 mmol) in CH.sub.2Cl.sub.2 (300 ml) at 0 C. was added trifluoroacetic acid (60 mL) dropwise. The resulting mixture was stirred at room temperature for 4 hours before concentration under reduced pressure. An aqueous solution of NaHCO.sub.3 (10%, 300 mL) was added to the residue which was extracted with EtOAc (300 mL). The extract was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using Petroleum Ether:EtOAc (3:1-0:1) as eluting solvents to afford 3H-imidazo[4,5-b]pyridin-3-amine as a yellow solid (12 g, 70%). MS (ESI) m/z: 135.1 [M+H].sup.+.

Step C. 4-(6-(3H-Imidazo[4,5-b]pyridin-3-ylamino)-3-cyanopyrazin-2-yl)phenyl sulfamate

[0321] The procedures described in Example 32 steps E, F and G were repeated using 3-(4-(benzyloxy)phenyl)-5-bromopyrazine-2-carbonitrile and 3H-imidazo[4,5-b]pyridin-3-amine to afford the title compound as a white solid (80 mg, 64%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 11.80 (s, 1H), 8.70 (s, 1H), 8.36 (d, J=4.3 Hz, 1H), 8.21 (d, J=8.1 Hz, 1H), 8.12 (s, 2H), 7.66 (s, 2H), 7.37 (m, 3H); MS (ESI) m/z: 409 [M+H].sup.+.

Example 41

6-(5-(1H-Benzo[d]imidazol-1-ylamino)-2-cyanophenyl)pyridin-3-yl sulfamate

[0322] The procedures described in Example 33 steps A, B and C were repeated using 4-(1H-benzo[d]imidazol-1-ylamino)-2-bromobenzonitrile (757 mg, 2.42 mmol) [Example 2 step B] and 2-(tributylstannyl)-5-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (1.24 g, 2.42 mmol) [Example 30 Step B] to afford the title compound as a brown solid (31 mg, 5%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 10.44 (s, 1H), 8.60 (d, 1H), 8.49 (s, 1H), 7.85-7.87 (m, 2H), 7.75-7.80 (m, 2H), 7.28-7.34 (m, 3H), 6.86 (s, 1H), 6.60 (d, 1H); MS (ESI) m/z: 407 [M+H].sup.+.

Example 42

6-((1H-Benzo[d]imidazol-1-yl)methyl)-3-cyano-[2,2-bipyridin]-5-yl sulfamate

Step A. 6-((1H-Benzo[d]imidazol-1-yl)methyl)-5-((2-(trimethylsilyl)ethoxy) methyoxy)-2,2-bipyridine-3-carbonitrile

[0323] A mixture of 6-((1H-benzo[d]imidazol-1-yl)methyl)-2-chloronicotinonitrile (1.2 g, 4.5 mmol) [see Example 10 Step B], 2-(tributylstannyl)-5-((2-(trimethylsilyl)ethoxy)methoxy)pyridine (2.3 g, 4.5 mmol) [Example 30 Step B], Pd(PPh.sub.3).sub.4 (260 mg, 0.225 mmol), LiCl (381 mg, 9 mmol), and CuI (171 mg, 0.9 mmol) in toluene (10 mL) was purged with nitrogen and heated at 120 C. overnight.

[0324] The reaction mixture was cooled to 23 C. and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography using Petroleum Ether:EtOAc (10:11:1) as eluting solvents to afford 6-((1H-benzo[d]imidazol-1-yl)methyl)-5-((2-(trimethylsilyl)ethoxy)-methyoxy)-2,2-bipyridine-3-carbonitrile as a brown solid (600 mg, 29%). MS (ESI) m/z: 458 [M+H].sup.+.

Step B. 6-((1H-Benzo[d]imidazol-1-yl)methyl)-5-hydroxy-2,2-bipyridine-3-carbonitrile

[0325] To a solution of 6-((1H-benzo[d]imidazol-1-yl)methyl)-5-((2-(trimethylsilyl)ethoxy)-methoxy)2,2-bipyridine-3-carbonitrile (654 mg, 2 mmol) in CH.sub.2Cl.sub.2 (40 mL) at room temperature was added CF.sub.3CO.sub.2H (2 mL). The mixture was stirred at 20 C. for 2 hours before evaporation of the solvent under reduced pressure. The residue was purified by preparative HPLC to afford 6-((1H-benzo[d]imidazol-1-yl)methyl)-5-hydroxy-2,2-bipyridine-3-carbonitrile as a white solid (350 mg, 82%). MS (ESI) m/z: 328 [M+H].sup.+.

Step C. 6-((1H-Benzo[d]imidazol-1-yl)methyl)-3-cyano-[2,2-bipyridin]-5-yl sulfamate

[0326] The procedure described in Example 1 step E was repeated using 6-((1H-benzo[d]imidazol-1-yl)methyl)-5-hydroxy-2,2-bipyridine-3-carbonitrile (350 mg, 1.07 mmol) and sulfamoyl chloride to afford the title compound as a white solid (281 mg, 65%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 8.63 (d, J=2.0 Hz, 1H), 8.57 (s, 1H), 8.45 (d, J=8.0 Hz, 1H), 8.34 (s, 2H), 8.09 (d, J=9.0 Hz, 1H), 7.92 (dd, J=2.5 Hz and J=8.5 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.26 (m, 2H), 5.84 (s, 2H); MS (ESI) m/z: 406 [M+H].sup.+.

Example 43

4-(5-(3H-Imidazo[4,5-b]pyridin-3-ylamino)-2-cyanopyridin-3-yl)phenyl sulfamate

[0327] Compound of Example 43 was prepared in the same manner as described for compound of Example 38 starting from 3-(4-(benzyloxy)phenyl)-5-chloropicolinonitrile and 3H-imidazo[4,5-b]pyridin-3-amine [see Example 40 Step A-E]. The title compound was obtained as a white solid (74 mg, 45%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.70 (s, 1H), 8.36 (m, 1H), 8.21 (dd, J=8.0 Hz, 1H), 8.14 (d, J=2.5 Hz, 1H), 7.61 (d, J=8.0 Hz, 2H), 7.38 (m, 3H), 6.87 (d, J=2.5 Hz, 1H); MS (ESI) m/z: 408 [M+H].sup.+.

Example 44

4-(6-((3H-Imidazo[4,5-b]pyridin-3-yl)(methyl)amino)-3-cyanopyrazin-2-yl)phenyl sulfamate

[0328] Compound of Example 44 was prepared in the same manner as described for compound of Example 34 starting from 5-(3H-imidazo[4,5-b]pyridin-3-ylamino)-3-(4-(benzyloxy)phenyl)pyrazine-2-carbonitrile. The title compound was obtained as a white solid (110 mg, 25.6%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.83 (s, 1H), 8.38 (d, J=4.7 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.18 (s, 2H), 7.92 (s, 2H), 7.44 (m, 3H), 3.80 (s, 3H); MS (ESI) m/z: 423 [M+H].sup.+.

Example 45

4-(5-((3H-Imidazo[4,5-b]pyridin-3-yl)(methyl)amino)-2-cyanopyridin-3-yl)phenyl sulfamate

[0329] Compound of Example 45 was prepared in the same manner as described for compound of Example 39 starting from 5-(3H-imidazo[4,5-b]pyridin-3-ylamino)-3-(4-(benzyloxy)phenyl)picolinonitrile. The title compound was obtained as a white solid (46 mg, 25%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.81 (s, 1H), 8.36 (d, J=4.5 Hz, 1H), 8.24 (d, J=7.5 Hz, 1H), 8.13 (s, 2H), 7.95 (d, J=2.5 Hz, 1H), 7.71 (d, J=8.5 Hz, 2H), 7.42 (m, 3H), 7.22 (d, J=2.5 Hz, 1H), 3.69 (s, 3H); MS (ESI) m/z: 422 [M+H].sup.+.

Example 46

4-(6-(3H-Imidazo[4,5-b]pyridin-3-ylamino)-3-cyanopyridin-2-yl)phenyl sulfamate

Step A. 6-(3H-imidazo[4,5-b]pyridin-3-ylamino)-2-(4-methoxyphenyl)nicotinonitrile

[0330] A mixture of 6-chloro-2-(4-methoxyphenyl)nicotinonitrile (3.0 g, 12.3 mmol), tert-butyl 3H-imidazo[4,5-b]pyridin-3-yl carbamate (2.88 g, 12.3 mmol) [see Example 40 Step A-D], Pd.sub.2(dba).sub.3 (563 mg, 0.615 mmol), xantphos (711 mg, 1.23 mmol), and Cs.sub.2CO.sub.3 (10.0 g, 30.75 mmol) in toluene (15 mL) in a sealed vial was purged with nitrogen and heated at 110 C. for 12 hours. The reaction mixture was cooled and purified by silica gel chromatography using Petroleum Ether:EtOAc (1:2-1:1) as eluting solvents to afford 6-(3H-imidazo[4,5-b]pyridin-3-ylamino)-2-(4-methoxy phenyl)nicotinonitrile (2 g, 47.6%). MS (ESI) m/z: 343 [M+H].sup.+.

Step B. 4-(6-(3H-Imidazo[4,5-b]pyridin-3-ylamino)-3-cyanopyridin-2-yl)phenyl sulfamate

[0331] The procedures described in Example 2 steps D and E were repeated using 6-(3H-imidazo[4,5-b]pyridin-3-ylamino)-2-(4-methoxy phenyl)nicotinonitrile to afford the title compound as a white solid (256 mg, 31%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm): 11.19 (s, 1H), 8.69 (s, 1H), 8.34 (dd, J=1.5 Hz, J=5.0 Hz, 1H), 8.20-8.11 (m, 5H), 7.64 (s, 2H), 7.35 (m, 3H); MS (ESI) m/z: 408 [M+H].sup.+.

Example 47

4-(2-(3H-Imidazo[4,5-b]pyridin-3-ylamino)-5-cyanopyrimidin-4-yl)phenyl sulfamate

Step A. 2-(3H-Imidazo[4,5-b]pyridin-3-ylamino)-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile

[0332] A mixture of 2-chloro-4-(4-methoxyphenyl) pyrimidine-5-carbonitrile (3.0 g, 12.2 mmol) [Example 10 Step C], tert-butyl 3H-imidazo[4,5-b]pyridin-3-yl carbamate (2.9 mg, 12.2 mmol) [see Example 40 Step A-D], Cs.sub.2CO.sub.3 (9.9 g, 30.5 mmol), Pd.sub.2(dba).sub.3 (558 mg, 0.61 mmol), and xantphos (1.80 mmol, 1.22 mmol) in 1,4-dioxane (15 mL) in a sealed vial was purged with nitrogen and heated at 110 C. for 12 hours. The reaction mixture was cooled and purified by silica gel chromatography using Petroleum Ether:EtOAc (1:1-1:2) as eluting solvents to afford 2-(3H-imidazo[4,5-b]pyridin-3-ylamino)-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile (3.00 g, 71%). MS (ESI) m/z: 343 [M+H].sup.+.

Step B. 4-(2-(3H-Imidazo[4,5-b]pyridin-3-ylamino)-5-cyanopyrimidin-4-yl)phenyl sulfamate

[0333] The procedures described in Example 2 steps D and E were repeated using 2-(3H-imidazo[4,5-b]pyridin-3-ylamino)-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile to afford the title compound as a white solid (123 mg, 13%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm): 11.87 (s, 1H), 813-8.68 (m, 2H), 8.36-8.09 (m, 5H), 7.60 (d, J=7.5 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.37 (s, 1H), 7.32 (d, J=8.0 Hz, 1H); MS (ESI) m/z: 409 [M+H].sup.+.

Example 48

4-(2-((3H-Imidazo[4,5-b]pyridin-3-yl)(methyl)amino)-5-cyanopyrimidin-4-yl)phenyl sulfamate

[0334] Compound of Example 48 was prepared in the same manner as described for compound of Example 5 starting from 2-(3H-imidazo[4,5-b]pyridin-3-ylamino)-4-(4-methoxyphenyl)pyrimidine-5-carbonitrile [see Example 47 Step A]. The title compound was obtained as a white solid (315 mg, 27%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm): 9.22-9.77 (m, 2H), 8.36 (d, J=3.5 Hz, 1H), 8.25-8.12 (m, 4H), 7.55 (s, 2H), 7.39 (m, 1H), 7.30 (s, 1H), 3.88 (s, 3H); MS (ESI) m/z: 423 [M+H].sup.+.

Example 49

4-(6-((3H-Imidazo[4,5-b]pyridin-3-yl)(methyl)amino)-3-cyanopyridin-2-yl)phenyl sulfamate

[0335] Compound of Example 49 was prepared in the same manner as described for compound of Example 5 starting from 6-(3H-imidazo[4,5-b]pyridin-3-ylamino)-2-(4-methoxyphenyl)nicotinonitrile [see Example 46 Step A].

[0336] The title compound was obtained as a white solid (177 mg, 24%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm): 8.82 (s, 1H), 8.37 (dd, J=1.5 Hz and 4.5 Hz, 1H), 8.25 (dd, J=1.0 Hz and 8.0 Hz, 1H), 8.17 (s, 2H), 8.08 (d, J=9.0 Hz, 1H), 7.87 (s, 2H), 7.43-7.40 (m, 3H); 6.41 (s, 1H), 3.77 (s, 3H). MS (ESI) m/z: 422 [M+H].sup.+.

Example 50

4-(5-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-cyanopyridin-3-yl)phenyl sulfamate

[0337] Compound of Example 50 was prepared in the same manner as described for compound of Example 31 starting from 3H-imidazo[4,5-b]pyridine. The title compound was obtained as a white solid (252 mg, 58%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.83 (d, 1H), 8.69 (s, 1H), 8.38 (q, 1H), 8.18 (s, 2H), 8.10-8.13 (m, 2H), 7.73 (q, 2H), 7.46 (q, 2H), 7.31 (q, 1H), 5.73 (s, 2H); MS (ESI) m/z: 407 [M+H].sup.+.

Example 51

4-(2-Cyano-5-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)pyridin-3-yl)phenyl sulfamate

[0338] Compound of Example 51 was prepared in the same manner as described for compound of Example 31 starting from 5,6-difluoro-1H-benzo[d]imidazole. The title compound was obtained as a brown solid (213 mg, 65%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 8.83 (d, 1H), 8.63 (s, 1H), 8.19 (s, 2H), 8.11 (d, 1H), 7.94 (q, 1H), 7.73-7.78 (m, 3H), 7.48 (d, 2H), 5.70 (s, 2H); MS (ESI) m/z: 442 [M+H].sup.+.

Example 52

4-(5-Cyano-2-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)pyrimidin-4-yl)phenyl sulfamate

[0339] Compound of Example 52 was prepared in the same manner as described for compound of Example 9 starting from 5,6-difluoro-1H-benzo[d]imidazole. The title compound was obtained as a white solid (148 mg, 10%). .sup.1H NMR (500 MHz, DMSO-d.sub.6) (ppm) 9.33 (s, 1H), 8.45 (s, 1H), 8.23 (s, 2H), 7.99 (d, J=9.0 Hz, 2H), 7.76 (t, J=8.8 Hz, 2H), 7.50 (dd, J=7.0 Hz, 2H), 5.95 (s, 2H); MS (ESI) m/z: 443 [M+H].sup.+.

[0340] Pharmacologic Study of the Compounds of the Present Invention

[0341] 1Aromatase and Steroid Sulfatase Inhibition

[0342] Aromatase and steroid sulfatase enzymes inhibitions were evaluated in the human chorionic carcinoma cell line JEG-3 which constitutively expresses high amount of aromatase and steroid sulfatase.

[0343] For aromatase inhibition assay, JEG-3 cells were seeded into 96-well plates at 35,000 cells/well and maintained in MEM containing supplements. When reaching 80% confluent, the cells were washed once with serum-free MEM, incubated with [1-.sup.3H] androstenedione (A4, 0.2 Ci/ml) for 1.25 hour in the presence of the test substances added in a concentration series. The product, tritiated water (.sup.3H.sub.2O), was separated using 2.5% (w/v) dextran-coated charcoal at 4-8 C. for 2 hours. The supernatant radioactivity was measured by a MicroBeta scintillation counter.

[0344] For STS assay, JEG-3 cells were seeded into 24-well culture plates at 150,000 cells/ml/well and maintained in MEM containing supplements overnight. When reaching 80% confluent, the cells were washed once with serum-free MEM, loaded with 1 ml of substrate mix containing [6,7-3H] Estrone sulfate (E1S, 0.6 Ci/ml) and [4-14C] Estrone (E1, 4 nCi/ml) in the presence of compounds in a concentration series, and incubated for 1 hour at 37 C. The product [3H]E1 was separated from E1S by toluene partition using [4-14C]E1 to monitor extraction procedural losses, and the toluene fraction radioactivity was measured by a MicroBeta scintillation counter.

[0345] Experiments are performed in duplicate. The inhibitory concentration of 50% of the enzymatic activity is calculated. Results for some examples are shown in the Table 1 below.

TABLE-US-00001 TABLE 1 Aromatase Inhibition Steroid Sulfatase Inhibition Example IC50 (nM) IC50 (nM) 1 1.2 2.0 2 2.0 6.8 3 * 18.9 4 4.8 12.1 5 3.2 25.6 6 53.2 * 7 * 16.4 8 6.3 23.6 9 3.5 1.8 10 3.2 9.1 11 1.2 18.4 12 0.5 7.0 13 13.1 * 14 7.0 21.7 15 17.5 14.6 16 6.4 22.0 17 2.2 3.9 18 1.2 26.4 19 2.2 * 20 2.9 52.3 21 2.2 * 22 3.7 6.0 23 6.5 7.1 24 0.9 2.0 25 6.2 10.7 26 2.7 11.8 27 4.6 17.8 28 5.8 * 29 2.5 37.6 30 5.9 7.2 31 4.6 10.5 32 37.6 19.5 33 9.0 17.6 34 8.4 35.7 35 5.1 29.4 36 2.0 10.5 37 2.4 41.8 38 2.7 19.1 39 1.5 * 40 * 18.8 41 2.0 9.3 42 41.9 * 43 11.8 * 44 5.8 * 45 2.1 * 46 21.7 39.5 47 56.1 44.1 48 5.8 * 49 3.7 * 50 16.3 * 51 2.2 15.5 52 2.9 5.4 *IC.sub.50 > 60 nM

[0346] 2Cytochrome P450 Inhibition

[0347] Inhibitory activity of the compounds towards CYP1A2, 2C9, 2C19, 2D6, and 3A4 was evaluated using human recombinant CYPs.

[0348] Test compounds and reference inhibitors were initially prepared from their stock solutions in a mixture solvent of DMSO/ACN (10/90) at a concentration of 200-fold of the final. A 3-fold serial dilution (1/3, 1/9, 1/27 etc.) was made in the DMSO/ACN mixture solvent to generate 7 consecutive concentrations. The serially diluted solutions of test compounds and reference inhibitors (positive controls) were further diluted directly in recombinant human CYP enzymes in assay buffer (0.1 M potassium phosphate buffer, pH7.4) to reach the concentration of 2-fold of the final (2).

[0349] Aliquots of 30 L of 2 compound/enzyme solutions were loaded to a 96-well assay plates and preincubated at 37 C. for 10 minutes. An aliquot of 15 L of prewarmed 4 substrate solutions made in the assay buffer was added into each of the wells containing the 2 compound/enzyme mixtures. Finally, the reaction was initiated by adding an aliquot of 15 L of 4NADPH made in the assay buffer and the assay plates were further incubated at 37 C. for a time period designated for each isoform (5 minutes for 3A4, 20 minutes for 2C9, 10 minutes for 2D6 and 2C19, and 15 minutes for 1A2). The reactions were stopped by adding 120 L ACN containing the stable isotopes of the metabolites for corresponding CYP isoforms, followed by vortexing for 5 minutes and centrifugation at 4000 rpm for 15 minutes. The resulting supernatants were transferred into new 96-well plates for LC-MS/MS analysis.

[0350] Experiments are performed in duplicate. The inhibitory concentration of 50% of the enzymatic activity is calculated. Results for some examples are shown in the Table 2 below.

TABLE-US-00002 TABLE 2 CYP1A2 IC50 CYP2C9 IC50 CYP2C19 IC50 CYP2D6 IC50 CYP3A4 IC50 Example (M) (M) (M) (M) (M) 9 >5 >5 >5 >5 3.68 17 >5 >5 >5 >5 >5 22 >5 >5 >5 >5 >5 24 >5 >5 >5 >5 3.26 26 >5 >5 >5 >5 2.54 31 >5 >5 >5 >5 >5 36 >5 >5 >5 >5 >5