1,2,4-TRIAZINE-4-AMINE DERIVATIVES

Abstract

According to the invention there is provided a compound of formula A1 which may be useful in the treatment of a condition or disorder ameliorated by the inhibition of the A.sub.1-A.sub.2b or, particularly, the A.sub.2a receptor wherein the compound of formula A1 has the structure, wherein, A represents Cy.sup.1 or Het.sup.A; Cy.sup.1 represents a 5- to 14-membered aromatic, fully saturated or partially unsaturated carbocyclic ring system comprising one, two or three rings, which Cy.sup.1 group is optionally substituted by one or more R.sup.4a substituents; Het.sup.A represents a 5- to 14-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more hetermatoms selected from O, S and N, which heterocyclic group may comprise one, two or three rings and which HetA group is optionally substituted by one or more R4b substituents; B represents a Cy.sup.2 or Het.sup.B; Cy.sup.2 represents a 3- to 10-membered aromatic, fully saturated or partially unsaturated carbocyclic ring system comprising one or two rings, which Cy.sup.2 group is optionally substituted by one or more R.sup.4c substituents; Het.sup.B represents a 3- to 10-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, which heterocyclic group may comprise one or two rings and which Het.sup.B group is optionally substituted by one or more R.sup.4d substituents.

##STR00001##

Claims

1-32. (canceled)

33. A pharmaceutical formulation comprising: 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable adjuvant, diluent, or carrier.

34. A pharmaceutical formulation comprising: a pharmaceutically acceptable salt of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; and a pharmaceutically acceptable adjuvant, diluent, or carrier.

35. A pharmaceutical formulation comprising: 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; and a pharmaceutically acceptable adjuvant, diluent, or carrier.

Description

EXAMPLES

[1002] Where no preparative routes are included, the relevant intermediate is commercially available (e.g. from Sigma Aldrich or Manchester Organics Ltd).

General Procedures

[1003] Commercial reagents were utilized without further purification. Room temperature refers to 20-27° C. Melting points, wherever reported, are uncorrected. .sup.1H-NMR spectra were recorded at 400 MHz on a Bruker instrument. Chemical shift values are expressed in parts per million, i.e. (6)-values. The following abbreviations are used for the multiplicity for the NMR signals: s=singlet, b=broad, d=doublet, t=triplet, q=quartet, qui=quintet, h=heptet, dd=doublet of doublets, dt=double of triplets, m=multiplet. Coupling constants are listed as J values, measured in Hz. NMR and mass spectroscopy results were corrected to account for background peaks. Chromatography refers to column chromatography performed using 60-120 mesh silica gel and executed under nitrogen pressure (flash chromatography) conditions. The TLC for monitoring the reaction means the TLC run using the specified mobile phase and the Silica gel F254 as a stationary phase from Merck. Microwave-mediated reactions were performed in a Biotage Initiator. HPLC purities were measured under the following conditions:

[1004] Instrument: Waters Alliance 2695. Column: Sunfire C-18, 250×4.6 mm, 5 μm, or equivalent. Gradient [time (min)/% solvent B in A]: 0.00/10, 9.00/90, 11.00/100, 20.00/100, 20.01/10, 25.00/10 (solvent A=0.1% formic acid in water; solvent B=0.1% formic acid in acetonitrile). 1 mL/min; detection wavelength specified for each compound in the detailed experimental section.

[1005] Mass spectroscopy was carried out on a Shimadzu LCMS-2010 EV, using electrospray conditions as specified for each compound in the detailed experimental section.

[1006] LCMS experiments were carried out with methods A-C, as specified for each compound in the detailed experimental section, using the following conditions:

[1007] LCMS method A: Instruments: Waters Alliance 2795, Waters 2996 PDA detector, Micromass ZQ. Column: Waters X-Bridge C-18, 2.5 micron, 2.1×20 mm or Phenomenex Gemini-NX C-18, 3 micron, 2.0×30 mm. Gradient [time (min)/solvent D in C (%)]: 0.00/2, 0.10/2, 2.50/95, 3.50/95, 3.55/2, 4.00/2 (solvent C=1.58 g ammonium formats in 2.5 L water+2.7 mL ammonia solution; solvent D=2.5 L Acetonitrile+132 mL (5%) solvent C+2.7 mL ammonia solution). Injection volume 5 uL; UV detection 230 to 400 nM; column temperature 45° C.

[1008] LCMS method B: Instrument: Waters Semi-Prep LCMS with ZQ MS. Column: Agilent Prep-C18 Scalar, 5 μm, 4.6×50 mm Detection wavelength: 254 nm and 215 nm. Gradient [time (min)/solvent B in A (%), flow rate]: 0.00/5 (2.5 mL/min), 0.10/5 (2.5 m/min), 5.0/95 (2.5 mL/min), 5.50/95 (2.5 mL/min), 5.60/95 (3.5 m/min), 6.60/95 (3.5 mL/min), 6.75/5 (3.5 mL/min) 6.90/5 (3.5 mL/min), 7.00/5 (2.5 mL/min). (solvent A: water with 0.1% NH.sub.4OH; solvent B: MeOH with 0.1% NH.sub.4OH).

[1009] LCMS method C: Instruments: Waters Alliance 2795. Waters 2996 PDA detector, Micromass ZQ. Column: Waters X-Bridge C-18, 2.5 micron, 2.1×20 mm or Phenomenex Gemini-NX C-18, 3 micron, 2.0×30 mm. Gradient [time (min)/solvent D in C (%)]: 0.00/2, 0.10/2, 8.40/95, 9.40/95, 9.50/2, 10.00/2 (solvent C=1.58 g ammonium formate in 2.5 L water+2.7 mL ammonia solution; solvent D=2.5 L Acetonitrile+132 mL (5%) solvent C+2.7 mL ammonia solution). Injection volume 5 uL; UV detection 230 to 400 nM; column temperature 45° C.: 1.5 mL/min.

[1010] Preparative HPLC was typically carried out with instrument A or B using an acidic method (gradients of acetonitrile and water, each containing 0.1% formic acid) or a basic method (gradients of methanol and water, each containing 0.1% NH.sub.4OH) Instrument A conditions: Waters delta 600 HPLC. Column: X-bridge C-18, 250×19 mm, 5 μm, or equivalent. Flow rate: 19 mL/min.

[1011] Instrument B: Gilson HPLC. Column: Agilent Zorbax Extend Cartridge, 5 μm, 21.2×100 mm. Guard Column: Agilent Prep-C18 Guard Cartridge, 10 μm. Flow rate: 28 mL/min.

Preparation 1

[1012] Procedure for the preparation of methyl Hydrazinecarbimidothioate

[1013] Methyl hydrazinecarbimidothioate was prepared by drop wise addition of methyl iodide (2.80 g, 19.8 mmol) to a solution of thiosemicarbazide (1.80 g, 19.75 mmol) in ethanol (50 mL). The resulting mixture was refluxed for 2.5 hrs with TLC monitoring (methanol/DCM, 1:9). The reaction mixture was then concentrated in vacuo and the crude compound (1.80 g, 90%) was used in the next step without any further purification.

[1014] Mass spectroscopy: (ESI +ve) 106 [M−H].sup.+

Typical Procedure for the Preparation of Arylglyoxal Derivatives, as Exemplified with (i) 4-Fluorophenylglyoxal

[1015] Selenium dioxide (6.70 g, 61.0 mmol) was added to a solution of 4-fluoroacetophenone (8.43 g, 61.0 mmol) in dioxane (100 mL) and water (3 mL), and the resulting mixture was heated at 55° C. until complete dissolution of selenium dioxide had occurred. The reaction mass was then refluxed for 5-6 hrs. After completion of the reaction (TLC), the mixture was filtered and the filtrate was concentrated in vacuo affording a viscous oil. Water (50 mL) was added and the resulting mixture was stirred for 12 hrs, after which time the solid was collected on a filter, washed with water (25 mL) and dried in vacuo, affording 4-fluorophenylglyoxal (6.60 g, 85%).

[1016] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 7.18 (m, 2H), 8.11 (d, 2H), aldehyde CHO signal not observed.

(ii) (3-Chloro-5-fluorophenyl)(oxo)acetaldehyde

[1017] (3-Chloro-5-fluorophenyl)(oxo)acetaldehyde (27 g, 84%) was prepared from 3-chloro-5-fluoro acetophenone (30.0 g, 174.4 mmol) and selenium dioxide (21.28 g, 191.8 mmol) according to the typical procedure used for Preparation 1.

(iii) (3,5-Difluorophenyl)(oxo)acetaldehyde

[1018] (3,5-Difluorophenyl)(oxo)acetaldehyde (28 g, 84%) was prepared from 3,5-difluoro acetophenone (30.0 g, 192.3 mmol) and selenium dioxide (23.55 g, 214.0 mmol) according to the typical procedure used for Preparation 1.

(iv) 4-(Methoxymethyl)phenylglyoxal

Step 1: Preparation of 4-(Methoxymethyl)benzonitrile

[1019] 4-(Hydroxymethyl) benzonitrile (6.0 g, 45.09 mmol) was dissolved in THF (60 mL), cooled to −5° C. to −10° C. and treated with sodium hydride (2.16 g, 90.19 mmol). The resulting mixture was stirred for 30 minutes then treated with methyl iodide (9.6 g, 67.65 mmol) at RT for 2 hours. After completion of the reaction (TLC: ethyl acetate/Hexane, 5:5), the mixture was poured into water (50 mL) and extracted with ethyl acetate (3×25 mL). The separated organic layers were combined, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude compound was purified by gradient flash chromatography, eluting with 5% ethyl acetate in hexane to afford 4-(methoxymethyl)benzonitrile (6.7 g, 90%).

[1020] HPLC purity: 99.20% (232 nm)

[1021] Mass spectroscopy: (ESI +ve) 148.0 [M+H].sup.+.

Step 2: Preparation of 1-[4-(methoxymethyl)phenyl]ethanone

[1022] 4-(Methoxymethyl)benzonitrile (6.0 g, 40.82 mmol) was dissolved in THF/diethyl ether (1:1, 60 mL) and the resulting solution was cooled to −10° C. 3 M solution of methyl magnesium iodide (13.57 g, 81.63 mmol) was added and the resulting mixture was stirred at this temperature for 5 hours. After completion of the reaction (TLC; toluene/methanol, 97:3), the mixture was poured into acidified water (50 mL; pH 3-4) and extracted with ethyl acetate (3×50 mL). The separated organic layers were combined, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude compound was purified by gradient flash chromatography, eluting with 8% ethyl acetate in hexane to afford the target compound (3.7 g, 55%).

[1023] Mass spectroscopy: (ESI +ve) 165.0 [M+H].sup.+.

Step 3: Preparation of 4-(methoxymethyl)phenylglyoxal

[1024] Selenium dioxide (3.53 g, 31.84 mmol) was dissolved in 1,4-dioxane (50 mL) and water (0.5 mL). The solution was warmed to 40° C. and treated with 1-(4-(methoxymethyl)phenyl)ethanone (3.9 g, 26.53 mmol); the resulting mixture was refluxed for 6 hours and monitored by TLC (chloroform/methanol, 95:5). After completion of the reaction, the mixture was filtered through celite and concentrated in vacuo. The crude compound was purified by column chromatography eluting with up to 15% ethyl acetate in hexane, affording the target glyoxal (4.0 g, 85%).

[1025] Mass spectroscopy: (ESI +ve) 179.0 [M−H].sup.+

(v) 2-Pyrimidineglyoxal

Step 1: Preparation of 1-(pyrimidin-2-yl)ethanone

[1026] A solution of 2-cyano-pyrimidine (10.0 g, 95.2 mmol) in THF (100 mL) was cooled to −5° C. and treated with a 3 M solution of methyl magnesium bromide in THF (38.0 mL, 98.4 mmol). The reaction was stirred at 0° C. for two hours until completion was observed by TLC (chloroform/methanol, 9:1). The reaction mixture was poured in water; the pH was adjusted to 5-6 and the aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic layers were concentrated under reduced pressure and the crude compound was purified by column chromatography, eluting with chloroform to afford the target compound (6.5 g, 48%).

[1027] HPLC purity: 97.2% (223 nm).

[1028] Mass spectroscopy: (ESI +ve) 123.1 [M+H].sup.+

Step 2: Preparation of 2-pyrimidineglyoxal

[1029] A solution of selenium dioxide (15 g, 135 mmol) in ethanol (150 mL) was stirred at 50° C. until a clear solution was obtained. 1-(Pyrimidin-2-yl)ethanone (10 g, 82.0 mmol) was added to the resulting mixture which was stirred for 6 hrs at 78° C. with TLC monitoring. This crude mixture was then used in next step without further purification.

[1030] Mass spectroscopy: (ESI +ve) 137.1 [M+H].sup.+

[1031] TLC R.sub.f: 0.3 (chloroform/methanol, 9:1)

(vi) 2-Pyridylglyoxal

[1032] 2-Pyridylglyoxal (8.0 g, crude) was prepared from selenium dioxide (15 g, 135 mmol) and 2-acetyl pyridine (10 g, 82 mmol) according to the typical procedure used for Preparation 1.

[1033] TLC R.sub.f: 0.1 (ethyl acetate)

[1034] Mass spectroscopy: (ESI +ve) 136.1 [M+H].sup.+.

(vii) 3-pyridylglyoxal

[1035] 3-Pyridylglyoxal (5.0 g, crude) was prepared from selenium dioxide (6.82 g, 61.4 mmol) and 3-acetyl pyridine (5.0 g, 41.0 mmol) according to the typical procedure used for Preparation 1.

[1036] Mass spectroscopy: (ESI +ve) 136.1 [M+H].sup.+

[1037] TLC R.sub.f: 0.1 (ethyl acetate)

[1038] Phenylglyoxal monohydrate is commercially available from Sigma Aldrich. 2,4-difluorophenylglyoxal and 3-methoxyphenylglyoxal are commercially available from Manchester Organics Ltd.

Preparation 2

[1039] ##STR00037##

General Procedure for the Preparation of 5-Aryl-1,2,4-Triazin-3-Amine Derivatives from Arylglyoxal Derivatives

[1040] Step 1: A solution of an arylglyoxal derivative (19.7 mmol) in ethanol (50 mL) is treated successively with sodium bicarbonate (3.32 g, 39.5 mol) and methyl hydrazinecarbimidothioate (19.7 mmol) and the resulting mixture is refluxed for 3 hrs. After completion of the reaction (TLC), the mixture is concentrated in vacuo, poured into water (50 mL), and extracted with DCM or ethyl acetate (2×25 mL). The combined organic extracts are then dried over Na.sub.2SO.sub.4, concentrated in vacuo, and purified by gradient flash chromatography, affording intermediate A, a 3-(methylsulfanyl)-5-aryl-1,2,4-triazine derivative.

[1041] Step 2: m-CPBA (7.44 g, 43.3 mmol) is added to a solution of intermediate A (14.4 mmol) in DCM (50 mL) at −20 to −15° C. and the resulting mixture is stirred at this temperature until the reaction is judged to be complete by TLC (typically 8 hrs). The reaction is then quenched with saturated aqueous NaHCO.sub.3 solution (100 mL) and extracted with ethyl acetate (2×25 mL). The combined organic extracts are dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The crude product, intermediate B, a 3-(methylsulfonyl)-5-aryl-1,2,4-triazine derivative, is purified by gradient flash chromatography.

[1042] Step 3: 0.5 M ammonia in THF (100 mL, 500 mmol) is cooled to −33° C. and treated with ferric nitrate (5.50 g, 13.6 mmol) for 10 minutes. A solution of intermediate B (13.6 mmol) in THF (15 mL) is then introduced by drop wise addition and the mixture is stirred for 4 hrs with monitoring by TLC (methano/DCM, 1:9). After completion of the reaction, the mixture is poured into water (150 mL) and extracted with DCM or ethyl acetate (2×50 mL). The combined organic extracts are then dried over Na.sub.2SO.sub.4, concentrated in vacuo and treated with 4N aqueous HCl solution (40-50 mL) for 10 minutes. The aqueous phase is then extracted with ethyl acetate (150 mL), neutralized with aqueous K.sub.2CO.sub.3 solution (90-100 mL), and re-extracted with ethyl acetate (100 mL). All of the organic extracts are then combined, dried over Na.sub.2SO.sub.4 and concentrated in vacuo, affording intermediate C, a 5-aryl-1,2,4-triazin-3-amine derivative.

(i) 5-Phenyl-1,2,4-triazin-3-amine

[1043] Step 1: 3-(Methylsulfanyl)-5-phenyl-1,2,4-triazine (2.93 g, 73%) was prepared from methyl hydrazinecarbimidothioate (2.07 g, 19.7 mmol) and phenylglyoxal monohydrate (2.89 g, 19.7 mmol) according to the general procedure of Preparation 2.

[1044] Mass spectroscopy: (ESI +ve) 204 [M+H].sup.+

[1045] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 2.73 (s, 3H), 7.53-7.60 (m, 3H), 8.14-8.17 (m, 2H), 9.38 (s, 1H).

[1046] Step 2: 3-(Methylsulfonyl)-5-phenyl-1,2,4-triazine (3.20 g, 96%) was prepared from 3-(methylsulfanyl)-5-phenyl-1,2,4-triazine (2.93 g, 14.4 mmol) and m-CPBA (7.44 g, 43.3 mmol) according to the general procedure of Preparation 2.

[1047] Mass spectroscopy: (ESI +ve) 236.9 [M+H].sup.+

[1048] Step 3: 5-Phenyl-1,2,4-triazin-3-amine (1.70 g, 73%) was prepared from 3-(methylsulfonyl)-5-phenyl-1,2,4-triazine (3.20 g, 13.6 mmol) and 0.5 M ammonia in THF (100 mL, 500 mmol) according to the general procedure of Preparation 2.

[1049] Mass spectroscopy: (ESI +ve) 172.9 [M+H].sup.+

[1050] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 7.30 (br s, 2H), 7.53-7.60 (m, 3H), 8.19-8.21 (dd, 2H), 9.20 (s, 1H).

(ii) 5-(2,4-Difluorophenyl)-1,2,4-triazin-3-amine

[1051] Step 1: 3-(Methylsulfanyl)-5-(2,4-difluorophenyl)-1,2,4-triazine (1.00 g, 78%) was prepared from methyl hydrazinecarbimidothioate (0.63 g, 6.0 mmol) and 2,4-difluorophenylglyoxal monohydrate (1.00 g, 6.0 mmol) according to the general procedure of Preparation 2.

[1052] Mass spectroscopy: (ESI +ve) 239.9 [M+H].sup.+

[1053] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 2.69 (s, 3H), 6.96-7.02 (m, 1H), 7.06-7.11 (m, 1H), 8.27-8.33 (m, 1H), 9.46 (s, 1H).

[1054] Step 2: 3-(Methylsulfonyl)-5-(2,4-difluorophenyl)-1,2,4-triazine (1.1 g, 97%) was prepared from 3-(methylsulfanyl)-5-(2,4-difluorophenyl)-1,2,4-triazine (1.00 g, 4.17 mmol) and m-CPBA (2.16 g, 4.17 mmol) according to the general procedure of Preparation 2.

[1055] Mass spectroscopy: (ESI +ve) 271.9 [M+H].sup.+

[1056] Step 3: 5-(2,4-Difluorophenyl)-1,2,4-triazin-3-amine (0.45 g, 53%) was prepared from 3-(methylsulfonyl)-5-(2,4-difluorophenyl)-1,2,4-triazine (1.10 g, 4.05 mmol) and 0.5 M ammonia in THF (50 mL, 25 mmol) according to the general procedure of Preparation 2.

[1057] Mass spectroscopy: (ESI +ve) 208.9 [M+H].sup.+

(iii) 5-(3-Methoxyphenyl)-1,2,4-triazin-3-amine

[1058] Step 1: 3-(Methylsulfanyl)-5-(3-methoxyphenyl)-1,2,4-triazine (1.01 g, 79%) was prepared from methyl hydrazinecarbimidothioate (0.58 g, 5.50 mmol) and 3-methoxyphenylglyoxal monohydrate (1.00 g, 5.50 mmol) according to the general procedure of Preparation 2.

[1059] Mass spectroscopy: (ESI +ve) 233.9 [M+H].sup.+

[1060] Step 2: 3-(Methylsulfonyl)-5-(3-methoxyphenyl)-1,2,4-triazine (0.90 g, 79%) was prepared from 3-(methylsulfanyl)-5-(3-methoxyphenyl)-1,2,4-triazine (1.00 g, 4.20 mmol) and m-CPBA (2.30 g, 12.8 mmol) according to the general procedure of Preparation 2.

[1061] Mass spectroscopy: (ESI +ve) 265.9 [M+H].sup.+

[1062] Step 3: 5-(3-Methoxyphenyl)-1,2,4-triazin-3-amine (0.31 g, 45%) was prepared from 3-(methylsulfonyl)-5-(3-methoxyphenyl)-1,2,4-triazine (0.90 g, 3.39 mmol) and 0.5 M ammonia in THF (50 mL, 25.0 mmol) according to the general procedure of Preparation 2.

[1063] Mass spectroscopy: (ESI +ve) 202.9 [M+H].sup.+

(iv) 5-(4-Fluorophenyl)-1,2,4-triazin-3-amine

[1064] Step 1: 3-(Methylsulfanyl)-5-(4-fluorophenyl)-1,2,4-triazine (6.00 g, 69%) was prepared from methyl hydrazinecarbimidothioate (4.51 g, 43.0 mmol) and 4-fluorophenylglyoxal monohydrate (6.60 g, 43.0 mmol) according to the general procedure of Preparation 2.

[1065] Mass spectroscopy: (ESI +ve) 221.9 [M+H].sup.+

[1066] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 2.73 (s, 3H), 7.24 (d, 2H), 8.18 (d, 2H), 9.34 (s, 1H).

[1067] Step 2: 3-(Methylsulfonyl)-5-(4-fluorophenyl)-1,2,4-triazine (5.00 g, 72%) was prepared from 3-(methylsulfanyl)-5-(4-fluorophenyl)-1,2,4-triazine (6.00 g, 27.0 mmol) and m-CPBA (12.4 g, 81.0 mmol) according to the general procedure of Preparation 2.

[1068] Mass spectroscopy: (ESI +ve) 253.9 [M+H].sup.+

[1069] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 3.55 (s, 3H), 7.34 (d, 2H), 8.33 (d, 2H), 9.82 (s, 1H).

[1070] Step 3: 5-(4-Fluorophenyl)-1,2,4-triazin-3-amine (2.80 g, 74%) was prepared from 3-(methylsulfonyl)-5-(4-fluorophenyl)-1,2,4-triazine (5.00 g, 19.7 mmol) and 0.5 M ammonia in THF (100 mL, 50.0 mmol) according to the general procedure of Preparation 2.

[1071] Mass spectroscopy: (ESI +ve) 191.0 [M+H].sup.+

[1072] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 6.79 (s, 2H), 7.40 (m, 2H), 8.23 (m, 2H), 9.21 (s, 1H).

(v) 5-[4-(methoxymethyl)phenyl]-1,2,4-triazin-3-amine

[1073] Step 1: 5-[4-(methoxymethyl)phenyl]-3-(methylsulfanyl)-1,2,4-triazine (4.0 g, 72%) was prepared from methyl hydrazinecarbimidothioate (7.33 g, 31.46 mmol) and 4-(methoxymethyl)phenylglyoxal (4 g, 22.47 mmol) according to the general procedure of Preparation 2.

[1074] Mass spectroscopy: (ESI +ve) 248.0 [M−H].sup.+

[1075] Step 2: 5-[4-(methoxymethyl)phenyl]-3-(methylsulfonyl)-1,2,4-triazine (3.5 g, 83%) was prepared from 5-[4-(methoxymethyl)phenyl]-3-(methylsulfanyl)-1,2,4-triazine (3.75 g, 15.2 mmol) and m-CPBA (7.92 g, 45.6 mmol) according to the general procedure of Preparation 2.

[1076] Mass spectroscopy: (ESI +ve) 279.9 [M−H].sup.+

[1077] Step 3: 5-[4-(methoxymethyl)phenyl]-1,2,4-triazin-3-amine (2.2 g, 85%) was prepared from 5-[4-(methoxymethyl)phenyl]-3-(methylsulfonyl)-1,2,4-triazine (3.40 g, 12.2 mmol) in THF (35 mL) and treated with NH.sub.3 gas by purging for 30 minutes, similarly to the general procedure of Preparation 2.

[1078] Mass spectroscopy: (ESI +ve) 217.0 [M+H].sup.+.

[1079] .sup.1H NMR: (400 MHz, DMSO) δ: 3.32 (s, 3H), 4.48 (s, 2H), 7.22 (s, 2H), 7.47 (d, 2H), 8.14 (d, 2H), 9.2 (s, 1H).

(vi) 5-(3-chloro-5-fluorophenyl)-1,2,4-triazin-3-amine

[1080] Step 1: 3-(methylsulfanyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine (16 g, 38.4%) was prepared from methyl hydrazinecarbimidothioate (25.5 g, 243 mmol) and 2-(3-chloro-5-fluorophenyl)-2-oxoacetaldehyde (30 g, 162 mmol) according to the general procedure of Preparation 2.

[1081] Mass spectroscopy: (ESI +ve) 255.9 [M−H].sup.+

[1082] Step 2: 3-(methylsulfonyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine (16 g, 88%) was prepared from 3-(methylsulfanyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine (16 g, 62.7 mmol) and m-CPBA (16.18 g, 94.11 mmol) according to the general procedure of Preparation 2.

[1083] Mass spectroscopy: (ESI +ve) 287.9 [M−H].sup.+

[1084] Step 3: 5-(3-chloro-5-fluorophenyl)-1,2,4-triazin-3-amine (1.70 g, 73%) was prepared from 3-(methylsulfonyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine (16.0 g, 55.5 mmol) and ammonia gas according to the general procedure of Preparation 2.

[1085] Mass spectroscopy: (ESI +ve) 224.9 [M−H].sup.+

(vii) 5-(3,5-difluorophenyl)-1,2,4-triazin-3-amine

[1086] Step-1: 3-(methylsulfanyl)-5-(3,5-difluorophenyl)-1,2,4-triazine (28 g, 80.0%) was prepared from methyl hydrazine carbimidothioate (20.68 g, 197.4 mmol) and 2-(3,5-difluorophenyl)-2-oxoacetaldehyde (25 g, 147.0 mmol) according to the general procedure of Preparation 2.

[1087] Mass spectroscopy: (ESI +ve) 240.0 [M−H].sup.+

[1088] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 2.74 (s, 3H), 7.02-7.07 (m, 1H), 7.69 (d, 2H), 9.32 (s, 1H).

[1089] Step-2: 3-(methylsulfonyl)-5-(3,5-difluorophenyl)-1,2,4-triazine (31 g, 97.7%) was prepared from 3-(methylsulfanyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine (28.0 g, 117.0 mmol) and m-chloro perbenzoicacid (40 g, 234 mmol) according to the general procedure of Preparation 2.

[1090] Mass spectroscopy: (ESI +ve) 271.9 [M−H].sup.+

[1091] Step-3: 5-(3,5-difluorophenyl)-1,2,4-triazin-3-amine (18 g, 74%) was prepared from 3-(methylsulfonyl)-5-(3,5-difluorophenyl)-1,2,4-triazine (31.0 g, 115.0 mmol) and ammonia gas according to the general procedure of Preparation 2.

[1092] Mass spectroscopy: (ESI +ve) 209.0 [M+H].sup.+.

[1093] .sup.1H NMR: (400 MHz, DMSO) δ: 7.37 (bs, 2H), 7.4 (m, 3H), 9.29 (s, 1H).

(viii) 5-(Pyrimidin-2-yl)-1,2,4-triazin-3-amine

[1094] Step 1: 3-(Methylsulfanyl)-5-(pyrimidin-2-yl)-1,2,4-triazine (5.0 g, 67%) was prepared from methylhydrazinecarbimidothioate (4.8 g 44.1 mmol) and 2-pyrimidineglyoxal (5.0 g, 37 mmol) according to the general procedure of Preparation 2.

[1095] Mass spectroscopy: (ES+I +ve) 206.0 [M+H].sup.+.

[1096] Step 2: 3-(Methylsulfonyl)-5-(pyrimidin-2-yl)-1,2,4-triazine (5.0 g, crude) was prepared from 3-(methylsulfanyl)-5-(pyrimidin-2-yl)-1,2,4-triazine (5.0 g, 24.3 mmol) and m-CPBA (10.5 g, 58.0 mmol) according to the general procedure of Preparation 2, without chromatographic purification.

[1097] Mass spectroscopy: (ESI +ve) 237.0 [M+H].sup.+.

[1098] TLC Rr: 0.5 (chloroform/methanol, 9:1) Step 3: 5-(Pyrimidin-2-yl)-1,2,4-triazin-3-amine (1.0 g, 23%) was prepared from 3-(methylsulfonyl)-5-(pyrimidin-2-yl)-1,2,4-triazine (5.0 g. crude) and 0.5 M ammonia in THF (20 mL) according to the general procedure of Preparation 2.

[1099] Mass spectroscopy: (ESI +ve) 175 [M+H].sup.+.

[1100] The following triazine intermediates were prepared from arylglyoxal derivatives in one step by condensation with aminoguanidine:

[1101] (ix) 5-(Pyridin-2-yl)-1,2,4-triazin-3-amine (1.5 g, 8% over 2 steps) was prepared from a crude sample of 2-pyridylglyoxal (8.0 g) and aminoguanidine hydrogen carbonate (6.0 g, 44 mmol). The reagents were refluxed in EtOH (100 mL) for 4 hours. The reaction mixture was then cooled, concentrated under reduced pressure and purified by gradient flash chromatography (eluting with 0-30% ethyl acetate/hexane). The sample contained a mixture of isomers at this stage and was used without further purification.

[1102] HPLC purity: 35%, (265 nm)

[1103] Mass spectroscopy: (ESI +ve) 174 [M+H].sup.+.

[1104] (x) 5-(Pyridin-3-yl)-1,2,4-triazin-3-amine (1.5 g, 16% over 2 steps) was prepared from a crude sample of 3-pyridylglyoxal (10.0 g) and aminoguanidine hydrogen carbonate (3.0 g, 22 mmol). The reagents were refluxed in EtOH (100 mL) for 4 hours. The reaction mixture was then cooled, concentrated under reduced pressure and purified by gradient flash chromatography (eluting with 0-30% ethyl acetate/hexane).

[1105] Mass spectroscopy: (ESI +ve) 174 [M+H].sup.+

[1106] TLC R.sub.f=0.2 (ethyl acetate)

[1107] The following 3-amino-5-aryl-1,2,4-triazine compounds are commercially available from UkrOrgSynth: [1108] 5-[4-(difluoromethoxy)phenyl]-1,2,4-triazin-3-amine; [1109] 5-(3-chloro-4-fluorophenyl)-1,2,4-triazin-3-amine; [1110] 5-(3-chlorophenyl)-1,2,4-triazin-3-amine; [1111] 5-(4-chlorophenyl)-1,2,4-triazin-3-amine; [1112] 5-(3,4-difluorophenyl)-1,2,4-triazin-3-amine; [1113] 5-(3-fluorophenyl)-1,2,4-triazin-3-amine; [1114] 4-(3-amino-1,2,4-triazin-5-yl)benzonitrile; [1115] 5-(4-ethylphenyl)-1,2,4-triazin-3-amine; [1116] 5-(4-methylphenyl)-1,2,4-triazin-3-amine; [1117] 5-(2-fluorophenyl)-1,2,4-triazin-3-amine; [1118] 5-(4-methoxyphenyl)-1,2,4-triazin-3-amine and [1119] 5-(2,5-difluorophenyl)-1,2,4-triazin-3-amine.

Preparation 3

[1120] ##STR00038##

General Procedure for the Halogenation of 5-Aryl-1,2,4-Triazin-3-Amine Derivatives

Method 1

[1121] A solution of intermediate C, a 5-aryl-1,2,4-triazin-3-amine derivative (8.70 mmol) in DMF (15 mL) is cooled to −25° C. and treated with a solution of N-chlorosuccinimide or N-bromosuccinimide (26.6 mmol) in DMF (10 mL) by drop wise addition. The reaction is stirred overnight and monitored by TLC (methanol/DCM, 1:9). After completion of the reaction, the mixture is poured into saturated bicarbonate solution (50 mL) and extracted with diethyl ether (25×3 mL). The organic phases are combined, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude compound is purified by gradient flash chromatography, eluting with mixtures of ethyl acetate in hexane (e.g. 10% ethyl acetate in hexane) to afford the target compound, intermediate D.

Method 2

[1122] A solution of intermediate C, a 5-aryl-1,2,4-triazin-3-amine derivative (8.70 mmol) in DMF (15 mL) is cooled to −25° C. and treated with a solution of N-chlorosuccinimide or N-bromosuccinimide (26.6 mmol) in DMF (10 mL) by drop wise addition. The reaction is stirred at room temperature and monitored by TLC or LCMS. After completion of the reaction, the mixture is poured into saturated bicarbonate solution (50 mL) and extracted with an organic solvent such as diethyl ether or ethyl acetate. The organic phases are combined, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude compound is purified by gradient flash chromatography, eluting with mixtures of ethyl acetate in hexane, or methanol in DCM, to afford the target compound, intermediate D.

(i) 6-Bromo-5-phenyl-1,2,4-triazin-3-amine

[1123] 6-Bromo-5-phenyl-1,2,4-triazin-3-amine (1.40 g, 64%) was prepared from 5-phenyl-1,2,4-triazin-3-amine (1.50 g, 8.70 mmol) and N-bromosuccinimide (4.50 g, 26.6 mmol) according to the general procedure of Preparation 3.

[1124] Mass spectroscopy: (ESI +ve) 251.9 [M+H].sup.+

[1125] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 5.49 (s, 2H), 7.49-7.58 (m, 3H), 7.82-7.85 (m, 2H).

(ii) 6-Chloro-5-phenyl-1,2,4-triazin-3-amine

[1126] 6-Chloro-5-phenyl-1,2,4-triazin-3-amine (0.38 g, 65%) was prepared from 5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and N-chlorosuccinimide (0.50 g, 3.7 mmol) according to the general procedure of Preparation 3.

[1127] Mass spectroscopy: (ESI +ve) 207.9 [M+H].sup.+

(iii) 6-Bromo-5-(2,4-difluorophenyl)-1,2,4-triazin-3-amine

[1128] 6-Bromo-5-(2,4-difluorophenyl)-1,2,4-triazin-3-amine (0.13 g, 21%) was prepared from 5-(2,4-difluorophenyl)-1,2,4-triazin-3-amine (0.45 g, 2.1 mmol) and N-bromosuccinimide (0.49 g, 2.80 mmol) according to the general procedure of Preparation 3.

[1129] Mass spectroscopy: (ESI +ve) 286.8 [M+H].sup.+

(iv) 6-Bromo-5-(3-methoxyphenyl)-1,2,4-triazin-3-amine

[1130] 6-Bromo-5-(3-methoxyphenyl)-1,2,4-triazin-3-amine (0.18 g, 42%) was prepared from 5-(3-methoxyphenyl)-1,2,4-triazin-3-amine (0.31 g, 1.50 mmol) and N-bromosuccinimide (0.35 g, 1.99 mmol) according to the general procedure of Preparation 3.

[1131] Mass spectroscopy: (ESI +ve) 280.9 [M+H].sup.+

(v) 6-Bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine

[1132] 6-Bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (1.95 g, 49%) was prepared from 5-(4-fluorophenyl)-1,2,4-triazin-3-amine (2.8 g, 14.00 mmol) and N-bromosuccinimide (7.87 g, 44.00 mmol) according to the general procedure of Preparation 3.

[1133] Mass spectroscopy: (ESI +ve) 268.9 [M+H].sup.+

[1134] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 5.43 (s, 2H), 7.19 (d, 2H), 7.87 (d, 2H).

[1135] The following intermediate compounds were also prepared according to the general procedure of Preparation 3:

TABLE-US-00001 No. Product (yield) Prepared From LCMS NMR (vi) 6-bromo-5-(3,4- 5-(3,4- Mass spectroscopy: (400 MHz, DMSO) δ: difluorophenyl)- difluorophenyl)-1,2,4- m/z 287, 289 (M + H).sup.+ 7.58-7.66 (m, 3H), 1,2,4-triazin-3-amine triazin-3-amine (2.8 g, (ES.sup.+); 285, 287 (M − H).sup.− 7.77-7.98 (m, 2H). (1.71 g, 44%) 13.45 mmol) (ES.sup.−), at 4.07 min, 100% (method B). (vii) 6-bromo-5-(3- 5-(3-fluorophenyl)- Mass spectroscopy: (400 MHz, DMSO) δ: fluorophenyl)-1,2,4- 1,2,4-triazin-3-amine m/z (Br) 269.6/271.7 7.38-7.47 (m, 1H), triazin-3-amine (1.27 (2.00 g, 10.52 mmol) (M + H).sup.+ (ES.sup.+); 7.51-7.70 (m, 5H). g, 44.9%) 267.9/269.9 (M − H).sup.− (ES.sup.−), at 3.85 min, 100% (method B). (viii) 6-bromo-5-(3- 5-(3-chlorophenyl)- Mass spectroscopy: (400 MHz, DMSO) δ: chlorophenyl)-1,2,4- 1,2,4-triazin-3-amine m/z (Br, Cl) 7.52-7.66 (m, 4H), triazin-3-amine (1.1 (2.00 g, 9.68 mmol) 285.7/287.7/289.7 7.69-7.73 (m, 1H), g, 40%) (M + H).sup.+ (ES.sup.+); 7.79 (t, J 1.7 Hz, 1H). 283.9/285.9/288.0 (M − H).sup.− (ES.sup.−), at 4.32 min, 100% (method B). (ix) 4-(3-amino-6-bromo- 4-(3-amino-1,2,4- Mass spectroscopy: (400 MHz, DMSO) δ: 1,2,4-triazin-5- triazin-5- m/z (Br) 276.6/278.6 7.66 (s, 2H), 7.86- yl)benzonitrile (605 yl)benzonitrile (2.00 (M + H).sup.+ (ES.sup.+); 7.94 (m, 2H), 7.99- mg, 21%) g, 10.14 mmol) 274.9/276.9 (M − H).sup.− 8.06 (m, 2H). (ES.sup.−), at 3.42 min, 98.6% (method B). (x) 6-bromo-5-(4- 5-(4-chlorophenyl)- Mass spectroscopy: (400 MHz, DMSO) δ: chlorophenyl)-1,2,4- 1,2,4-triazin-3-amine m/z (Br, Cl) 7.58 (s, 2H), 7.60- triazin-3-amine (890 (2.00 g, 9.68 mmol) 285.0/287.0/289.0 7.65 (m, 2H), 7.74- mg, 32%) (M + H).sup.+ (ES.sup.+); 7.81 (m, 2H). 283.2/285.2/287.2 (M − H).sup.− (ES.sup.−), at 4.32 min, 98.0% (method B). (xi) 6-bromo-5-(4- 5-(4- Mass spectroscopy: (400 MHz, DMSO) δ: (difluoromethoxy)phe- (difluoromethoxy)phe- m/z 317, 319 (M + H).sup.+ 7.30-7.36 (m, 2H), nyl)-1,2,4-triazin-3- nyl)-1,2,4-triazin-3- (ES.sup.+); 315-, 317 (M − H).sup.− 7.39 (t, 2JHF 72 Hz, amine (1.32 g, 50%) amine (2 g, 8.40 (ES.sup.−), at 3.98 min, 1H), 7.57 (s, 2H), mmol) 100% purity method B. 7.81-7.87 (m, 2H). (xii) 6-bromo-5-[4- 5-[4- HPLC purity: 98.35% (400 MHz, DMSO) δ: (methoxymethyl)phe- (methoxymethyl)phe- (242 nm); Mass 3.33 (s, 3H), 4.48 (s, nyl]-1,2,4-triazin-3- nyl]-1,2,4-triazin-3- spectroscopy: (ESI +ve) 2H), 7.44 (d, 2H), amine (1.3 g, 43%) amine (2.2 g, 15.2 295.0 [M + H].sup.+. 7.54 (b s, 2H), 7.72 mmol) (d, 2H). (xiii) 6-bromo-5-(3-chloro- 5-(3-chloro-4- Mass spectroscopy: (400 MHz, DMSO) δ: 4-fluorophenyl)- fluorophenyl)-1,2,4- m/z 303, 305 (M + H).sup.+ 7.54-7.70 (m, 3H), 1,2,4-triazin-3-amine triazin-3-amine (2.2 g, (ES.sup.+); 301, 303 (M − H).sup.− 7.80 (ddd, J 8.6, 4.7, (1.12 g, 36%) 9.79 mmol) (ES.sup.−), at 4.35 min, 2.2 Hz, 1H), 7.99 (dd, 100% purity method B. J 7.2, 2.2 Hz, 1H). (xiv) 6-bromo-5-(3-chloro- 5-(3-chloro-5- HPLC purity: 99.01% (400 MHz, CDCl.sub.3) δ: 5-fluorophenyl)- fluorophenyl)-1,2,4- (247 nm); Mass 5.53 (bs, 2H), 7.27 1,2,4-triazin-3-amine triazin-3-amine (16.0 spectroscopy: (ESI +ve) (m, 1H), 7.48 (m, 1H), (8.0 g, 38%) g, 55.55 mmol) 304.0 [M + H].sup.+. 7.64 (m, 1H). (xv) 6-bromo-5-(3,5- 5-(3,5- HPLC purity: 97.88% (400 MHz, CDCl.sub.3) δ: difluorophenyl)- difluorophenyl)-1,2,4- (247 nm); Mass 7.48 (m, 3H), 7.62 (s, 1,2,4-triazin-3-amine triazin-3-amine (18.0 spectroscopy: (ESI +ve) 2H). (6.0 g, 24%) g, 62.0 mmol) 286.8 [M + H].sup.+. (xvi) 6-bromo-5- 5-(pyrimidin-2-yl)- HPLC purity: 99.08% (400 MHz, DMSO) δ: (pyrimidin-2-yl)- 1,2,4-triazin-3-amine Mass spectroscopy: 7.73 (t, 1H), 7.79 (s, 1,2,4-triazin-3-amine (1.0 g, 5.75 mmol) (ESI +ve) 253. [M + H].sup.+. 2H), 9.04 (d, 2H) (0.90 g, 64%) and N- bromosuccinimide (1.53 g, 8.60 mmol) (xvii) 6-bromo-5-(pyridin- 5-(pyridin-2-yl)-1,2,4- Mass spectroscopy: 2-yl)-1,2,4-triazin-3- triazin-3-amine (0.30 (ESI +ve) 253. [M + H].sup.+. amine (0.18 g, 41%) g, 1.73 mmol) and N- TLC R.sub.f: 0.6 (ethyl bromosuccinimide acetate) (0.46 g, 2.60 mmol) (xviii) 6-bromo-5-(pyridin- 5-(pyridin-3-yl)-1,2,4- TLC R.sub.f: 0.6 (ethyl 3-yl)-1,2,4-triazin-3- triazin-3-amine (0.4 g, acetate) amine (0.19 g, 33%) 2.3 mmol) and N- Mass spectroscopy: bromosuccinimide (ESI +ve) 253. [M + H].sup.+. (0.61 g, 3.4 mmol) (xix) 6-bromo-5-(4- 5-(4-methylphenyl)- Mass spectroscopy: m/z (400 MHz, DMSO) δ: methylphenyl)-1,2,4- 1,2,4-triazin-3-amine 265.0/267.0 (M + H).sup.+ 3.35 (s, 3H), 7.41 (m, triazin-3-amine (450 (930 mg, 5.0 mmol) (ESI+) at 3.0 min, >95% 2H), 7.74 (m, 2H) mg, 34%) and N- (method C). (NH.sub.2 not observed). bromosuccinimide (2.67 g, 15.0 mmol) (xx) 6-bromo-5-(4- 5-(4-ethylphenyl)- Mass spectroscopy: m/z ethylphenyl)-1,2,4- 1,2,4-triazin-3-amine 279.0/281.0 (M + H).sup.+ triazin-3-amine (500 (930 mg, 5.0 mmol) (ESI+) at 3.48 min, mg, crude; used and N- 90% (method C). without bromosuccinimide TLC R.sub.f: 0.11 chromatographic (2.67 g, 15.0 mmol) (MeOH/DCM, 3:97) purification) (xxi) 6-bromo-5-(2- 5-(2-fluorophenyl)- TLC R.sub.f: 0.4 (400 MHz, DMSO) fluorophenyl)-1,2,4- 1,2,4-triazin-3-amine (EtOAc:isohexane 1:1) δ: 7.32-7.42 (m, 2H), triazin-3-amine (700 (2.5 g, 13.2 mmol) 7.54-7.67 (m, 4H) mg, 20%) and N- bromosuccinimide (7.05 g, 39.6 mmol) (xxii) 6-bromo-5-(2,5- 5-(2,5- Mass spectroscopy: (400 MHz, DMSO) difluorophenyl)- difluorophenyl)-1,2,4- m/z 288.9 (.sup.81Br) δ: 7.43-7.86 (m, 5H) 1,2,4-triazin-3-amine triazin-3-amine (2.5 g, (M + H).sup.+ (ES.sup.+), at 1.29 (800 mg, 27%) 10.4 mmol) and N- min, 100% (method A) bromosuccinimide (7.05 g, 39.6 mmol) (xxiii) 6-bromo-5-(4- 5-(4-methoxyphenyl)- TLC R.sub.f: 0.4 (400 MHz, DMSO) methoxyphenyl)- 1,2,4-triazin-3-amine (EtOAc:isohexane 1:1) δ: 3.83 (s, 3H), 7.08 1,2,4-triazin-3-amine (2.5 g, 12.4 mmol) (d, J 9.0, 2H), 7.47- (600 mg, 17%) and N- 7.54 (bs, 2H), 7.80 (d, bromosuccinimide J 9.0, 2H) (7.05 g, 39.6 mmol)

Preparation 4

[1136] 4a: General Procedure for S.sub.NAr Displacements of 2-Chloropyridine Derivatives with Amines

[1137] A 2-chloropyridine derivative (1 equivalent) and an amine (typically 5 equivalents) were dissolved in MeCN and sealed in a microwave vial. The mixture was heated under microwave irradiation (typically 160-180° C.) for up to 1 hour with LCMS monitoring. If necessary, further equivalents of amine were added and the procedure repeated. Upon completion of the reaction, the mixture was evaporated under reduced pressure and purified by flash column chromatography, eluting with ethyl acetate/hexane mixtures, or by preparative HPLC.

[1138] The following intermediate compounds were prepared according to the general procedure of Preparation 4a:

TABLE-US-00002 No. Product (yieid) Prepared from LC/MS NMR (i) 2- 2-Chloro-6- Mass ethyl(methyl)amino- methylpyridine (0.87 spectroscopy: m/z 6-methylpyridine mL, 7.84 mmol) and 151 (M + H).sup.+ (ES+) at (534 mg, 45%) ethylmethylamine 1.56 min, 95% (3.37 mL, 39.2 mmol) (method A) TLC R.sub.f: 0.55 (EtOAc/ isohexane, 1:20) (ii) 2-dimethylamino-6- 2-Chloro-6- Mass methylpyridine (93 methylpyridine (0.35 spectroscopy: m/z mg, 21%). mL, 3.20 mmol) and 137 (M + H).sup.+ (ES).sup.+ at dimethylamine (2.0M 1.37 min (method A) solution in THF, TLC R.sub.f: 0.38 (Et.sub.2O/ 8.0 mL, 16.0 mmol) isohexane, 1:20) (iii) 2-(azetidin-1-yl)-6- 2-Chloro-6- Mass (400 MHz, CDCl.sub.3) δ: (trifluoromethyl)pyri- trifluoromethylpyridine spectroscopy: m/z 2.41 (quint., J7.5, dine (807 mg, 72%) (1.00 g, 5.51 mmol) (ES.sup.+) 223.0 (M + H).sup.+ 2H), 4.08 (t, J7.5, and azetidine (1.57 g, at 1.68 min, 4H), 6.36-6.39 (m, 1.86 ml, 27.5 mmol) 90% (method A) 1H), 6.89-6.91 (m, 1H), 7.49-7.53 (m, 1H). (iv) 4-(6-methylpyridin- 2-Chloro-6- Mass (400 MHz, CDCl.sub.3) δ: 2-yl)morpholine methylpyridine spectroscopy: m/z 2.41 (s, 3H), 3.48- (693 mg, 50%) (1.00 g, 0.87 ml, (ES.sup.+) 179.0 (M + H).sup.+ 3.50 (m, 4H), 3.81- 7.84 mmol) and at 1.26 min, 3.84 (m, 4H), 6.42- morpholine (3.41 g, 90% (method A). 6.44 (m, 1H), 6.53- 3.45 ml, 39.2 mmol) 6.55 (m, 1H), 7.38- 7.42 (m, 1H).

4b: Preparation of Other Pyridine Derivatives

(i) Preparation of 2,6-d.SUB.6.-dimethylpyridine

[1139] Methyl-d.sub.3-magnesium iodide solution (9.60 mL, 1 M in diethyl ether, 9.60 mmol) was added drop-wise over 10 mins to a solution of 2,6-dibromopyridine (947 mg, 4.00 mmol) and iron(III)acetylacetonate (141 mg, 0.40 mmol) in THF (30 mL) and NMP (3 mL) under N.sub.2. After stirring at ambient temperature for 40 mins. 1 M aqueous HCl (10 mL) was added and the mixture stirred for 5 mins. Diethyl ether (20 mL) was added and the phases were separated. The organic phase was extracted with water (2×10 mL) and the combined aqeuous phases were then basified by the addition of 1M aqueous NaOH (15 mL). The aqueous phase was extracted with DCM (3×25 mL) and the combined organic phases concentrated in vacuo. Purification by gradient flash chromatography (SiO.sub.2, 5 to 20% EtOAc in isohexane) yielded the title compound as a clear oil (430 mg, 95%).

[1140] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 6.95 (d, J=7.8, 2H), 7.45 (t, J=7.8, 1H).

[1141] TLC R.sub.f: 0.30 (EtOAc/isohexane, 1:4)

(ii) Preparation of 2-dimethyl-6-(trifluoromethyl)pyridine

[1142] A mixture of 2-chloro-6-(trifluoromethyl)pyridine (2.69 g, 14.8 mmol) and iron(III)acetylacetonate (523 mg, 1.48 mmol) in THF (100 mL) and NMP (10 mL) was stirred at 0° C. under N.sub.2 for 5 mins. Methyl-d.sub.3-magnesium iodide solution (18.0 mL, 1M in diethyl ether, 18.0 mmol) was added drop-wise over 10 mins, and the mixture was stirred under N.sub.2 at 0° C. for 5 mins, then ambient temperature for 75 mins. 1 M aqueous HCl (50 mL) was added and the mixture was stirred for 5 mins before addition of diethyl ether (50 mL) and separation of the phases. The organic phase was washed with 0.5 M aqueous HCl (50 mL) and water (50 mL) and the combined aqueous phases were extracted with diethyl ether (2×50 mL). The combined organic phases were concentrated to a volume of approximately 25 mL and short path distillation (bp 28-30° C. at 35 mbar) yielded a clear oil to which was added DCM (5 mL) and H.sub.2O (5 mL). The phases were separated and the aqueous phase was extracted with DCM (2×5 mL); the combined organic phases were concentrated in vacuo to yield the title compound (639 mg, 26%) as a clear oil.

[1143] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 7.34 (d, J 7.8, 1H), 7.49 (d, J 7.8, 1H), 7.75 (t, J 7.8, 1H).

[1144] Bp: 28-30° C. at 35 mbar

(iii) Preparation of 2-cyclopropyl-6-(trifluoromethyl)pyridine

[1145] 2-Chloro-6-trifluoromethyl pyridine (451 mg, 2.5 mmol), cyclopropyltrifluoroborate potassium salt (373 mg, 2.52 mmol), palladium acetate (11 mg, 0.05 mmol), di(1-adamantyl)-n-butylphosphine (27 mg, 0.075 mmol), and cesium carbonate (2.4 g, 7.5 mmol) were suspended in a mixture of toluene and water (10:1, 10 mL). After flushing the vessel under a stream of nitrogen gas for 5 minutes, the reaction tube was sealed and then heated at 100° C. for 18 hours. On cooling, the mixture was partitioned between DCM (15 mL) and water (15 mL). The separated aqueous phase was extracted with DCM (2×15 mL) and the combined organic phases were passed through a phase separator and concentrated in vacuo, affording a yellow oi which was used without further purification (423 mg, crude).

[1146] LCMS: major peak observed at 1.77 min; poor ionisation (method A)

[1147] TLC R.sub.f: 0.6 (EtOAc/hexane, 1:9).

(iv) Preparation of 2-ethyl-6-(trifluoromethyl)pyridine

[1148] 2-Chloro-6-trifluoromethyl pyridine (451 mg, 2.5 mmol), ethyltrifluoroborate potassium salt (374 mg, 2.75 mmol), palladium acetate (11 mg, 0.05 mmol), di(1-adamantyl)-n-butylphosphine (27 mg, 0.075 mmol), and cesium carbonate (2.4 g, 7.5 mmol) were suspended in a mixture of toluene and water (10:1, 10 mL). After flushing the vessel under a stream of nitrogen gas for 5 minutes, the reaction tube was sealed and then heated at 100° C. for 18 hours. On cooling, the mixture was partitioned between DCM (15 mL) and water (15 mL). The separated aqueous phase was extracted with DCM (2×15 mL) and the combined organic phases were passed through a phase separator and concentrated in vacuo, affording a yellow oil which was used without further purification (460 mg, crude)

[1149] LCMS: major peak observed at 1.53 min; poor ionisation (method A)

[1150] TLC R.sub.f: 0.55 (EtOAc/hexane, 1:9).

(v) Preparation of 2-ethylamino-6-methylpyridine

[1151] 2-Amino-6-methylpyridine (1.00 g, 9.25 mmol) and acetaldehyde (0.52 mL, 9.34 mmol) were stirred together in anhydrous methyl alcohol for 1 hour at room temperature under a nitrogen atmosphere. The mixture was then treated with sodium triacetoxyborohydride (7.84 g, 37.0 mmol) and five drops of acetic acid and all was allowed to continue stirring for 4 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and DCM, and the separated aqueous phase was extracted twice with DCM. The combined organics were dried over MgSO.sub.4, filtered and concentrated in vacuo to give a mobile oil which was purified by flash column chromatography, eluting with 2% MeOH/DCM, to give 2-ethylamino-6-methylpyridine (636 mg, 51%).

[1152] LCMS: 137.0 [M+H].sup.+ (ES+) at 1.17 min, 100% (method A).

Preparation 5

General Procedure for the Preparation of 2-Fluoromethylpyridine Derivatives

[1153] (Diethylamino)sulfur trifluoride (1.0 mL, 7.7 mmol) was added to a solution of a 2-pyridinylmethanol derivative (7.0 mmol) in DCM (30 mL, anhydrous), drop-wise, under nitrogen in an acetone/CO.sub.2 bath at −20° C. The resultant solution was allowed to warm to ambient temperature and then stirred until complete conversion was observed by TLC. The reaction was quenched with ice and then basified to pH 8-10 with solid sodium hydrogen carbonate. The layers were then separated, and the organic phase washed successively with water and then saturated brine solution, then dried (MgSO.sub.4), concentrated in vacuo and purified by gradient flash chromatography, affording the 2-fluoromethylpyridine derivative.

[1154] The following intermediate compounds were prepared according to the general procedure of Preparation 5:

TABLE-US-00003 No. Product (yield) Prepared from LCMS/TLC NMR (i) 2-(fluoromethyl)-6- 6-methyl-2- TLC R.sub.f: 0.9 (400 MHz, DMSO) methylpyridine (850 mg, pyridine (EtOAc/iso- δ: 2.48 (s, 3H), 5.43 (d, 84%) methanol (1.0 g, hexane 1:9) J 47.2 2H), 7.23 (d, J 8.1 mmol) 7.8, 1H), 7.29 (d, J 7.8, 1H), 7.76 (t, J 7.8, 1H) (ii) 2-chloro-6- (6-chloro-2- TLC R.sub.f: 0.9 (400 MHz, DMSO) (fluoromethyl)pyridine pyridinyl)methanol (EtOAc/iso- δ: 5.51 (d, J 46.7 Hz, (200 mg, 17%) (1.0 g, 7.0 hexane 1:9) 2H), 7.55 (d, J 7.78, mmol) 1H), 7.57 (d, J 7.78, 1H), 8.00 (t, J 7.78, 1H) (iii) 2,6-bis- 2,6- TLC R.sub.f: 0.9 (400 MHz, DMSO) (fluoromethyl)pyridine bis(hydroxymeth- (EtOAc/iso- δ: 5.50 (d, J 46.6, 2H), (850 mg, 41%) yl)pyridine (2.0 hexane 1:9) (d, J 7.78, 2H), 7.98 (t, g, 14.4 mmol) J 7.78, 1H)

Preparation 6

General Procedure for the Preparation of 2-Difluoromethylpyridine Derivatives

[1155] (Diethylamino)sulfur trifluoride (2.4 mL, 18.3 mmol) was added to a solution of a 2-pyridinecarboxaldehyde derivative (8.3 mmol) in DCM (30 mL, anhydrous), drop-wise, under nitrogen in an acetone/CO.sub.2 bath at −20° C. The resultant solution was allowed to warm to ambient temperature and then stirred until complete conversion was observed by TLC. The reaction was quenched with ice and then basified to pH 8-10 with solid sodium hydrogen carbonate. The layers were then separated, and the organic phase washed successively with water and then saturated brine solution, then dried (MgSO.sub.4), concentrated in vacuo and purified by gradient flash chromatography, affording the 2-fluoromethylpyridine derivative.

[1156] The following intermediate compounds were prepared according to the general procedure of Preparation 6:

TABLE-US-00004 No. Product (yield) Prepared from LCMS/TLC NMR (i) 2-chloro-6- 6-chloro-2- TLC R.sub.f: 0.9 (400 MHz, DMSO), δ: (difluoromethyl)pyridine pyridinecarboxal- (EtOAc/ 4.69 (s, 1H), 7.50 (m, (1.1 g, 86%) dehyde (1.0 g, isohexane 2H), 7.91 (m, 1H) 7.07 mmol) 1:9) (ii) 2-(difluoromethyl)-6- 6-methyl-2- TLC R.sub.f: 0.9 (400 MHz, DMSO), δ: methylpyridine (410 mg, pyridinecarboxal- (EtOAc/ 2.53 (3H, s) 6.90 (d, J 35%) dehyde (1.0 g, isohexane 55.2, 1H), 7.47 (m, 8.26 mmol) 1:9) 2H), 7.89 (m, 1H)

Preparation 7

General Procedure for the 4-Borylation of 2,6-Disubstituted Pyridine Derivatives

[1157] Methoxy(cyclooctadiene)rhodium(I) dimer (0.05 molar equivalents Rh). 4,4′-di-tert-butyl-2,2′-bipyridine(dtbpy) (0.05 molar equivalents), and bis(pinacolato)diboron (2 molar equivalents) were added to a flask which had been thoroughly purged with nitrogen. The flask was once more purged before adding hexane via syringe (final concentration of pyrine approximately 0.5 mM). The resulting mixture was heated at 50° C. for 10 minutes until the appearance of a dark red solution was observed. A pyridine derivative (1 molar equivalent) was then added by syringe and heating continued for a further 6 hours. After cooling to room temperature, the crude reaction mixture concentrated under reduced pressure. The resulting residue was purified by column chromatography, eluting with ethyl acetate/hexane mixtures to afford the target compound.

[1158] The following compounds were prepared according to the general procedure of Preparation 7, by reacting the indicated starting materials for 6 hours at 50° C., unless otherwise stated:

TABLE-US-00005 No. Product (yield) Prepared from LCMS/TLC NMR (i) 2,6-d.sub.6-dimethyl-4- bis(pinacolato)diboron Mass (4,4,5,5-tetramethyl- (1.93 g, 7.60 mmol) and spectroscopy: 1,3,2-dioxaborolan- 2,6-d.sub.6-dimethylpyridine m/z 240.1 2-yl)pyridine (1.56 g, (430 mg, 3.80 mmol) [M + H].sup.+ (ESI +ve) crude) used without were heated at 70° C. for at 0.1 min, chromatographic 105 minutes according to 100% (method purification the typical procedure. A). (ii) 2-d.sub.3-methyl-4- 2-d.sub.3-methyl-6- Mass (400 MHz, (4,4,5,5-tetramethyl- (trifluoromethyl)pyridine spectroscopy: CDCl.sub.3) δ: 1.37 1,3,2-dioxaborolan- (639 mg, 3.89 mmol) and m/z: 291.1 (s, 12H), 7.70 2-yl)-6- bis(pinacolato)diboron [M + H].sup.+ (ESI +ve) (s, 1H), 7.82 (trifluoromethyl)pyri- (1.98 g, 7.80 mmol) were at 0.15 (s, 1H). dine (716 mg, 32%) heated at 70° C. for 3.5 min, 100% hours according to the (method A) typical procedure. (iii) 2-ethylamino-4- bis(pinacolato) diborane Mass (4,4,5,5-tetramethyl- (776 mg, 3.06 mmol) and spectroscopy: 1,3,2-dioxaborolan- 2-ethylamino-6- m/z 263.2 2-yl)-6- methylpyridine (277 mg, [M + H].sup.+ (ESI+) at methylpyridine 2.04 mmol) were heated 0.10 min, (crude sample used to 55° C. for 6 hours (method A). without according to the typical chromatographic procedure. purification) (iv) 2- bis(pinacolato)diboron Mass ethyl(methyl)amino- (1.81 g, 7.11 mmol) and spectroscopy: 4-(4,4,5,5- 2-ethyl(methyl)amino-6- m/z 277 (M + H).sup.+ tetramethyl-1,3,2- methylpyridine (534 mg, (ES).sup.+ at 1.11 dioxaborolan-2-yl)-6- 3.55 mmol) were heated min, (method A). methylpyridine (2.04 at 65° C. for 3 hours g, crude) used according to the typical without procedure. chromatographic purification. (v) 2-dimethylamino-4- 2-dimethylamino-6- No ionisation (4,4,5,5-tetramethyl- methylpyridine (93 mg, observed by 1,3,2-dioxaborolan- 0.68 mmol) and LCMS, major 2-yl)-6- bis(pinacolato)diboron peak at 0.8 min methylpyridine (414 (348 mg g, 1.37 mmol) (method A). mg, crude) used were heated at 70° C. for without 2 hours according to the chromatographic typical procedure. purification. (vi) 2-chloro-4-(4,4,5,5- 2-methyl-6-chloro HPLC purity: (400 MHz, tetramethyl-1,3,2- pyridine (25 g, 195.9 99.33% (282 nm) DMSO) δ: 1.30 dioxaborolan-2-yl)-6- mmol) and Mass (s, 12 H), 2.50 methylpyridine (46.9 bis(pinacolato)diboron spectroscopy: (s, 3H), 7.35 g, 94%) (32.3 g, 127 mmol) (ESI +ve) 254.1 (s, 1H), 7.44 according to the typical [M + H].sup.+. (s, 1H). procedure. (vii) 2,6-dimethyl-4- 2,6-dimethyl pyridine (1.5 HPLC purity: (400 MHz, (4,4,5,5-tetramethyl- g, 13.9 mmol) and 93.33% (268 nm) DMSO) δ: 1.27 1,3,2-dioxaborolan- bis(pinacolato)diboron Mass (s, 12 H), 2.48 2-yl)pyridine (1.0 g, (1.9 g, 7.69 mmol) spectroscopy: (s, 6H), 7.20 30%) according to the typical (ESI +ve) 234.1 (s, 2H). procedure. [M + H].sup.+. (viii) 2-(trifluoromethyl)-4- 2-trifluoromethyl-6- HPLC purity: (400 MHz, (4,4,5,5-tetramethyl- methyl pyridine (4.0 g, 95.65% (210 nm) DMSO) δ: 1.31 1,3,2-dioxaborolan- 24.8 mmol) and Mass (s, 12 H), 2.51 2-yl)-6- bis(pinacolato)diboron spectroscopy: (s, 3H), 7.70 methylpyridine (5.9 (4.09 g, 16.1 mmol) (ESI +ve) 287.8 (s, 1H), 7.76 g, 83%) according to the typical [M + H].sup.+. (s, 1H). procedure. (ix) 2-dimethylamino-4- N,N-dimethylpyridine-2- Mass (4,4,5,5-tetramethyl- amine (0.9 g, 7.4 mmol) spectroscopy: 1,3,2-dioxaborolan- and (ESI +ve) 248.9 2-yl)pyridine (0.98 g, bis(pinacolato)diboron [M].sup.+). 53%) (1.12 g, 4.4 mmol) TLC R.sub.f: 0.10 according to the typical (ethyl acetate/ procedure. hexane, 5:5) (x) 2-bromo-4-(4,4,5,5- 2-methyl-6-bromo Mass tetramethyl-1,3,2- pyridine (0.50 g, 2.90 spectroscopy: dioxaborolan-2-yl)-6- mmol) and (ESI +ve) 299.7 methylpyridine (0.70 bis(pinacolato)diboron [M + H].sup.+ g, 81%) (0.48 g, 1.8 mmol) TLC R.sub.f: 0.15 according to the typical (ethyl acetate/ procedure. hexane, 5:5) (xi) 2-cyano-4-(4,4,5,5- 2-methyl-6-cyano Mass tetramethyl-1,3,2- pyridine (0.5 g, 4.2 spectroscopy: dioxaborolan-2-yl)-6- mmol) and (ESI +ve) 244.9 methylpyridine (0.70 bis(pinacolato)diboron [M + H].sup.+ g, 70%) (0.69 g, 2.7 mmol), TLC R.sub.f: 0.15, (ethyl acetate/ hexane, 5:5) (xii) 1-oxo-2,6-dimethyl- 2,6-dimethyl pyridine-N- Mass 4-(4,4,5,5- oxide (1.0 g, 8.12 mmol) spectroscopy: tetramethyl-1,3,2- and (ESI +ve) 249.9 dioxaborolan-2- bis(pinacolato)diboron [M].sup.+ yl)pyridine (1.8 g, (1.34 g, 5.27 mmol) TLC R.sub.f: 0.12 90%) (ethyl acetate/ hexane, 5:5) (xiii) 2-bromo-4-(4,4,5,5- 2-trifluoro methyl 6- Mass tetramethyl-1,3,2- bromo pyridine (0.5 g, spectroscopy: dioxaborolan-2-yl)-6- 2.20 mmol) and (ESI +ve) 352.9 trifluoromethylpyridine bis(pinacolato)diboron [M].sup.+). (0.5 g, 64%) (0.36 g, 1.4 mmol) TLC R.sub.f: 0.18 according to the typical (ethyl acetate/ procedure. hexane, 5:5) (xiv) 2-chloro-4-(4,4,5,5- 2-chloro-6- TLC R.sub.f: streak (400 MHz, tetramethyl-1,3,2- (difluoromethyl)pyridine from baseline to DMSO) dioxaborolan-2-yl)-6- (1.4 g, 8.56 mmol) and 0.3 (EtOAc/ δ: 1.33 (s, (difluoromethyl)pyridine bis(pinacolato)diboron isohexane, 1:9) 12H), 7.03 (t, J (310 mg, 13%) (10.1 g, 42.8 mmol) were 54.5, 1H), 7.75 heated at 60° C. for 2 (s, 1H), 7.80 hours according to the (s, 1H) typical procedure. (xv) 2-(fluoromethyl)-4- 2-(fluoromethyl)-6- Mass (400 MHz, (4,4,5,5-tetramethyl- methylpyridine (2.1 g, spectroscopy: DMSO) 1,3,2-dioxaborolan- 16.8 mmol) and (ESI +ve) 252.1 δ: 1.32 (s, 2-yl)-6- bis(pinacolato)diboron [M + H].sup.+ at 0.13 12H), 2.55 (s, methylpyridine (1.1 (8.5 g, 33.6 mmol) were mins, (method 3H), 5.45 (d, J g, 26%) heated at 60° C. for 48 A). 47.2, 2H), 7.45 hours according to the (s, 1H), 7.47 typical procedure. (s, 1H) (xvi) 2-chloro-4-(4,4,5,5- 2-chloro-6- TLC R.sub.f: streak (400 MHz, tetramethyl-1,3,2- (fluoromethyl)pyridine from baseline to DMSO) dioxaborolan-2-yl)-6- (1.0 g, 6.9 mmol) and 0.3 (EtOAc/ δ: 1.33 (s, (fluoromethyl)pyridine bis(pinacolato)diboron isohexane, 1:9) 12H), 5.50(d, J (450 mg, 24%) (3.5 g, 13.8 mmol) were 46.7, 2H), 7.57 heated at 60° C. for 2 (s, 1H), 7.65 hours according to the (s, 1H) typical procedure. (xvii) 2,6-bis- 2,6-bis- TLC R.sub.f: streak (400 MHz, (fluoromethyl)-4- fluoromethylpyridine from baseline to DMSO) (4,4,5,5-tetramethyl- (1.2 g, 6.8 mmol) and 0.3 δ: 1.22 (s, 1,3,2-dioxaborolan- bis(pinacolato)diboron (EtOAc/isohexane, 12H), 5.50 (d, 2-yl)-pyridine (1.6 g, (3.5 g, 13.6 mmol) were 1:9) J 46.7, 4H), 88%) heated at 65° C. for 2 7.51 (s, 2H) hours according to the typical procedure. (xviii) 2-(difluoromethyl)-4- 2-(difluoromethyl)-6- TLC R.sub.f: streak (400 MHz, (4,4,5,5-tetramethyl- methylpyridine (1.2 g, 8.4 from baseline to DMSO) 1,3,2-dioxaborolan- mmol) and 0.3 δ: 1.32 (s, 2-yl)-6- bis(pinacolato)diboron (EtOAc/isohexane, 12H), 2.55 (s, methylpyridine (500 (4.3 g, 16.8 mmol) were 1:9) 3H), 6.94 (t, J mg, 22%) heated at 60° C. for 2 55, 1H), 7.61 hours according to the (s, 1H), 7.63 typical procedure. (s, 1H) (xix) 2-ethyl-4-(4,4,5,5- 2-ethyl-6- Mass (400 MHz, tetramethyl-1,3,2- (trifluoromethyl)pyridine spectroscopy: DMSO) δ: 1.25 dioxaborolan-2-yl)-6- (440 mg, 2.50 mmol) and m/z 302.1 (t, 3H, J 8.0), (trifluoromethyl)pyridine bis(pinacolato)diboron (M + H).sup.+ (ES+); 1.33 (s, 12H), (551 mg, 73%) (1.27 g, 5.00 mmol) at 0.93 min 2.88 (q, 2H, J according to the typical (method A). 8.0), 7.74 (s, procedure. 1H), 7.77 (s, 1H). (xx) 2-cyclopropyl-4- 2-cyclopropyl-6- Mass (400 MHz, (4,4,5,5-tetramethyl- (trifluoromethyl)pyridine spectroscopy: DMSO) δ: 0.92- 1,3,2-dioxaborolan- (423 mg, 2.25 mmol) and m/z 314.1 0.97 (m, 2H), 2-yl)-6- bis(pinacolato)diboron (M + H).sup.+ (ES+); 1.02-1.08 (m, (trifluoromethyl)pyridine (1.14 g, 4.50 mmol) at 1.02 min 2H), 1.33 (s, (473 mg, 67%) according to the typical (method A). 12H), 2.29- procedure. 2.36 (m, 1H), 7.63 (s, 1H), 7.79 (s, 1H). (xxi) 2-(azetidin-1-yl)-6- 2-(azetidin-1-yl)-6- Mass (400 MHz, trifluoromethyl-4- (trifluoromethyl)pyridine spectroscopy: CDCl.sub.3) δ: 1.31 (4,4,5,5-tetramethyl- (807 mg, 3.99 mmol) and m/z 329.0 (s, 12H), 2.35 1,3,2-dioxaborolan- bis(pinacolato)diboron (M + H).sup.+ (ES.sup.+), at (quint., J 7.5, 2-yl)pyridine (68%) (2.03 g, 7.98 mmol) were 1.00 min, 2H), 4.03 (t, J heated at 70° C. for 2.0 98% (method 7.5 Hz, 4H), hours according to the A). 6.74 (s, 1H), typical procedure. 7.06 (s, 1H). (xxii) 2-methyl-6- 4-(6-methylpyridin-2- Mass (morpholin-4-yl)-4- yl)morpholine spectroscopy: (4,4,5,5-tetramethyl- (693 mg, 3.89 mmol) m/z 305.0 1,3,2-dioxaborolan- and (M + H).sup.+ (ES.sup.+), at 2-yl)pyridine (1.09 g, bis(pinacolato)diboron 2.02 min, ~80% 92%) (1.97 g, 7.78 mmol) were (method A). heated at 70° C. for 4.0 TLC R.sub.f: 0.3 hours according to the (DCM/MeOH, typical procedure 1:9 (5% NH.sub.3)) (xxiii) 2-chloro-4-(4,4,5,5- bis(pinacolato)diboron HPLC purity (400 MHz, tetramethyl-1,3,2- (1.99 g, 7.9 mmol) and 2- purity: 95.87% DMSO) δ: 1.31 dioxaborolan-2-yl)-6- trifluoromethyl-6- (273 nm) (s, 12 H), 7.88 trifluoromethylpyridine chloropyridine (2.2 g, Mass (s, 1H), 7.89 (2.6 g, 68%). 12.1 mmol) spectroscopy: (s, 1H). (ESI +ve) 308.1[M + H].sup.+.

Example 1

[1159] ##STR00039##

General Procedure for the Preparation of 5,6-Biaryl-3-amino-1,2,4-triazines

[1160] A solution of intermediate D, a 6-halo-5-aryl-1,2,4-triazin-3-amine derivative. (0.80 mmol) in dioxane (2 mL) is treated with an arylboronic acid (0.92 mmol) and K.sub.2CO.sub.3 (0.23 g, 1.67 mmol). The resulting mixture is diluted with water (1.0 mL), degassed, treated with tetrakis triphenylphosphine palladium (0.05 g, 0.04 mmol) and stirred at 150° C. for 2.25 hrs with monitoring by TLC (hexane/ethyl acetate, 5:5). Upon completion of the reaction, the mixture is diluted with water (30 mL) and extracted with ethyl acetate (3×20 mL); the combined organic extracts are then dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude compound, product A, is purified by gradient flash chromatography or preparative HPLC.

(i) 5,6-Diphenyl-1,2,4-triazin-3-amine

[1161] 5,6-Diphenyl-1,2,4-triazin-3-amine (86.0 mg, 42%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.8 mmol) and phenyl boronic acid (0.11 g, 0.92 mmol) according to the general procedure of Example 1.

[1162] HPLC purity: 99.6% (261 nm)

[1163] Mass spectroscopy: (ESI +ve) 249.0 [M+H].sup.+.

[1164] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 5.49 (s, 2H), 7.30-7.37 (m, 5H), 7.40-7.43 (m, 3H,) 7.45-7.46 (m, 1H), 7.47-7.51 (m, 1H).

(ii) 6-(3-Methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine

[1165] 6-(3-Methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (106 mg, 47%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.8 mmol) and 3-methoxyphenyl boronic acid (0.137 g, 0.90 mmol) according to the general procedure of Example 1.

[1166] HPLC purity: 99.58% (223 nm)

[1167] Mass spectroscopy: (ESI +ve) 278.9 [M+H].sup.+.

[1168] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 3.72 (s, 3H), 5.47 (s, 2H), 6.88-6.94 (m, 2H), 7.03 (m, 1H), 7.20 (t, 1H), 7.33 (m, 2H), 7.40 (m, 1H), 7.44 (m, 2H).

(iii) 6-(4-Fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine

[1169] 6-(4-Fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine (99 mg, 46%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and 4-fluorophenylboronic acid (0.112 g, 0.80 mmol) according to the general procedure of Example 1.

[1170] HPLC purity: 99.93% (261 nm)

[1171] Mass spectroscopy: (ESI +ve) 267.0 [M+H].sup.+.

[1172] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 5.49 (s, 2H), 6.99 (m, 2H), 7.31-7.37 (m, 2H), 7.37-7.46 (m, 5H).

(iv) 6-(5-Chloro-2-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine

[1173] 6-(5-Chloro-2-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (57 mg, 22%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and 5-chloro-2-methoxyphenylboronic acid (0.15 g, 0.80 mmol) according to the general procedure of Example 1.

[1174] HPLC purity: 98.73% (229 nm)

[1175] Mass spectroscopy: (ESI +ve) 312.9 [M].sup.+.

[1176] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 3.16 (s, 3H), 5.46 (s, 2H), 6.62 (d, 1H), 7.26-7.33 (m, 3H), 7.37 (m, 1H), 7.44 (m, 2H), 7.66 (d, 1H).

(v) 6-(2-Chlorophenyl)-5-phenyl-1,2,4-triazin-3-amine

[1177] 6-(2-Chlorophenyl)-5-phenyl-1,2,4-triazin-3-amine (103 mg, 45%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and 2-chlorophenylboronic acid (0.125 g, 0.80 mmol) according to the general procedure of Example 1.

[1178] HPLC purity: 99.27% (245 nm)

[1179] Mass spectroscopy: (ESI +ve) 282.9 [M].sup.+.

[1180] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 5.62 (s, 2H), 7.26-7.32 (m, 2H), 7.33-7.36 (m, 4H) 7.43-7.45 (m, 2H), 7.52 (m, 1H).

(vi) 6-(3-Chlorophenyl)-5-phenyl-1,2,4-triazin-3-amine

[1181] 6-(3-Chlorophenyl-5-phenyl-1,2,4-triazin-3-amine (110 mg, 49%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and 3-chlorophenylboronic acid (0.12 g, 0.80 mmol) according to the general procedure of Example 1.

[1182] HPLC purity: 93.7% (261 nm)

[1183] Mass spectroscopy: (ESI +ve) 282.9 [M].sup.+.

[1184] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 5.50 (s, 2H), 7.18-7.26 (m, 2H), 7.30-7.36 (m, 3H) 7.42-7.47 (m, 3H), 7.53 (s, 1H).

(vii) 6-(4-Chlorophenyl-5-phenyl-1,2,4-triazin-3-amine

[1185] 6-(4-Chlorophenyl-5-phenyl-1,2,4-triazin-3-amine (125 mg, 56%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and 4-chlorophenylboronic acid (0.12 g, 0.80 mmol) according to the general procedure of Example 1.

[1186] HPLC purity: 97.7% (264 nm)

[1187] Mass spectroscopy: (ESI +ve) 282.9 [M].sup.+

[1188] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 5.46 (s, 2H), 7.28-7.33 (m, 2H), 7.35-7.38 (m, 5H) 7.42-7.46 (m, 2H).

(viii) 6-(Furan-2-yl)-5-phenyl-1,2,4-triazin-3-amine

[1189] 6-(Furan-2-yl)-5-phenyl-1,2,4-triazin-3-amine (100 mg, 35%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.3 g, 1.19 mmol) and 2-fluoroboronic acid (0.16 g, 1.428 mmol) according to the general procedure of Example 1.

[1190] HPLC purity: 95.03% (290 nm)

[1191] Mass spectroscopy: (ESI +ve) 239.0 [M+H].sup.+

[1192] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 5.58 (s, 2H), 6.43 (m, 1H), 6.55 (m, 1H) 7.40-7.47 (m, 3H), 7.47-7.59 (m, 3H).

(ix) 5-Phenyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazin-3-amine

[1193] 5-Phenyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazin-3-amine (120 mg, 31%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3-trifluoromethylphenylboronic acid (0.25 g, 1.30 mmol) according to the general procedure of Example 1.

[1194] HPLC purity: 99.4% (262 nm)

[1195] Mass spectroscopy: (ESI +ve) 316.9 [M+H].sup.+

[1196] .sup.1H NMR: (400 MHz, DMSO) δ: 7.36 (m, 4H), 7.42 (m, 2H), 7.51 (s, 2H) 7.56 (m, 1H), 7.63 (m, 3H).

(x) 6-[3-Fluoro-5-(trifluoromethyl)phenyl]-5-phenyl-1,2,4-triazin-3-amine

[1197] 6-[3-Fluoro-5-(trifluoromethyl)phenyl]-5-phenyl-1,2,4-triazin-3-amine (149 mg, 37%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3-fluoro-5-(trifluoromethyl)phenylboronic acid (0.27 g, 1.30 mmol) according to the general procedure of Example 1.

[1198] HPLC purity: 94.3% (265 nm)

[1199] Mass spectroscopy: (ESI +ve) 335.0 [M+H].sup.+

[1200] .sup.1H NMR: (400 MHz, DMSO) δ: 7.36 (m, 4H), 7.45 (m, 3H), 7.61 (s, 2H) 7.64 (d, 1H).

(xi) 5-Phenyl-6-(3,4,5-trifluorophenyl)-1,2,4-triazin-3-amine

[1201] 5-Phenyl-6-(3,4,5-trifluorophenyl)-1,2,4-triazin-3-amine (131 mg, 37%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3,4,5-trifluorophenylboronic acid (0.23 g, 1.30 mmol) according to the general procedure of Example 1.

[1202] HPLC purity: 99.6% (262 nm)

[1203] Mass spectroscopy: (ESI +ve) 303.0 [M+H].sup.+, (ESI −ve) 301.2 [M−H].sup.−

[1204] .sup.1H NMR: (400 MHz, DMSO) δ: 7.24 (t. 2H), 7.38 (m, 4H), 7.44 (m, 1H), 7.56 (s, 2H).

(xii) 6-(3,5-Difluorophenyl)-5-phenyl-1,2,4-triazin-3-amine

[1205] 6-(3,5-Difluorophenyl)-5-phenyl-1,2,4-triazin-3-amine (160 mg, 47%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3,5-difluorophenylboronic acid (0.20 g, 1.30 mmol) according to the general procedure of Example 1.

[1206] HPLC purity: 99.3% (262 nm)

[1207] Mass spectroscopy: (ESI +ve) 284.9[M+H].sup.+, (ESI −ve) 283.1 [M−H].sup.−

[1208] .sup.1H NMR: (400 MHz, DMSO) δ: 6.99 (d, 2H), 7.12 (t, 1H), 7.40 (m, 5H) 7.56 (s, 2H).

(xiii) 6-(3,5-Dichlorophenyl)-5-phenyl-1,2,4-triazin-3-amine

[1209] 6-(3,5-Dichlorophenyl)-5-phenyl-1,2,4-triazin-3-amine (130 mg, 34%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3,5-dichlorophenylboronic acid (0.42 g, 2.19 mmol) according to the general procedure of Example 1.

[1210] HPLC purity: 90% (245 nm)

[1211] Mass spectroscopy: (ESI +ve) 316.9[M+H].sup.+, (ESI −ve) 315.1 [M−H].sup.−

[1212] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 5.55 (s, 2H), 7.33 (m, 3H), 7.38 (m, 2H) 7.49 (m, 3H).

(xiv) 6-(5-Chloropyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine

[1213] 6-(5-Chloropyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine (35 mg, 10%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 5-chloropyridine-3-ylboronic acid (0.20 g, 1.30 mmol) according to the general procedure of Example 1.

[1214] HPLC purity: 98.9% (262 nm)

[1215] Mass spectroscopy: (ESI +ve) 283.9 [M+H].sup.+.

[1216] .sup.1H NMR: (400 MHz, DMSO) δ: 7.38 (m, 4H), 7.45 (m, 1H), 7.61 (s, 2H), 7.87 (t, 1H), 8.35 (d, 1H), 8.55 (d, 1H).

(xv) 6-(3-Chloro-4-fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine

[1217] 6-(3-Chloro-4-fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine (140 mg, 29%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol) and 3-chloro-4-fluorophenylboronic acid (0.33 g, 1.91 mmol) according to the general procedure of Example 1.

[1218] HPLC purity: 93.7% (261 nm)

[1219] Mass spectroscopy: (ESI +ve) 300.9 [M+H].sup.+.

[1220] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 5.49 (s, 2H), 7.04 (t, 1H), 7.18 (m, 1H), 7.37 (m, 2H), 7.45 (m, 3H), 7.60 (dd, 1H).

(xvi) 6-(3-Chloro-5-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine

[1221] 6-(3-Chloro-5-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (36 mg, 9%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3-chloro-5-methoxyphenylboronic acid (0.27 g, 1.43 mmol) according to the general procedure of Example 1.

[1222] HPLC purity: 99% (254 nm)

[1223] Mass spectroscopy: (ESI +ve) 312.9 [M+H].sup.+.

[1224] .sup.1H NMR: (400 MHz, DMSO) δ: 3.63 (s, 3H), 6.78 (m, 1H), 6.94 (m, 2H), 7.34-7.45 (m, 5H), 7.49 (bs, 2H).

(xvii) 6-(3-Fluoro-5-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine

[1225] 6-(3-Fluoro-5-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (193 mg, 32%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and 3-fluoro-5-methoxy phenylboronic acid (0.37 g, 2.19 mmol) according to the general procedure of Example 1.

[1226] HPLC purity: 99.6% (263 nm)

[1227] Mass spectroscopy: (ESI +ve) 296.9 [M+H].sup.+.

[1228] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 3.69 (s, 3H), 5.56 (s, 2H), 6.59 (d, 1H) 6.70 (d, 1H), 6.78 (s, 1H), 7.35 (m, 2H), 7.45 (m, 3H).

(xviii) 6-(1H-Indol-6-yl)-5-phenyl-1,2,4-triazin-3-amine

[1229] 6-(1H-Indol-6-yl)-5-phenyl-1,2,4-triazin-3-amine (107 mg, 23%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.4 g, 1.59 mmol) and indol-6-boronic acid (0.256 g, 1.59 mmol) according to the general procedure of Example 1.

[1230] HPLC purity: 97.75% (222 nm)

[1231] Mass spectroscopy: (ESI +ve) 288.0 [M+H].sup.+

[1232] .sup.1H NMR: (400 MHz, DMSO) δ: 6.38 (m, 1H), 6.89 (dd, 1H), 7.26-7.40 (m, 3H), 7.42-7.62 (m, 5H), 11.12 (s, 1H).

(xix) 6-(3-Bromophenyl)-5-phenyl-1,2,4-triazin-3-amine

[1233] 6-(3-Bromophenyl)-5-phenyl-1,2,4-triazin-3-amine (218 mg, 52%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.4 g, 1.59 mmol) and 3-bromophenylboronic acid (0.32 g, 1.59 mmol) according to the general procedure of Example 1.

[1234] HPLC purity: 95.65% (262 nm)

[1235] Mass spectroscopy: (ESI +ve) 326.9 [M+H].sup.+

[1236] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 5.61 (s, 2H), 7.15 (t, 1H), 7.24 (m, 1H), 7.35 (m, 2H), 7.47 (m, 4H), 7.69 (t, 1H).

(xx) 6-(3,4-Dichlorophenyl)-5-phenyl-1,2,4-triazin-3-amine

[1237] 6-(3,4-Dichlorophenyl)-5-phenyl-1,2,4-triazin-3-amine (52 mg, 54%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3,4-dichlorophenylboronic acid (65.5 mg, 0.344 mmol) according to the general procedure of Example 1.

[1238] HPLC purity: 99.2% (254 nm)

[1239] Mass spectroscopy: (ESI +ve) 317.1/319.1/321.1 (M+H).sup.+

[1240] .sup.1H NMR: (400 MHz, d6-DMSO) δ: 7.24 (dd. 1H), 7.35-7.47 (m, 5H), 7.53 (bs, 2H), 7.57 (m, 1H), 7.63 (d, 1H).

(xxi) 6-(3-Fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine

[1241] 6-(3-Fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine (49 mg, 62%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3-fluorophenylboronic acid (48.1 mg, 0.344 mmol) according to the general procedure of Example 1.

[1242] HPLC purity: 100% (254 nm)

[1243] Mass spectroscopy: (ESI +ve) 267.1 (M+H).sup.+

[1244] .sup.1H NMR: (400 MHz, d6-DMSO) δ:7.10-7.20 (m, 3H), 7.31-7.44 (m, 6H), 7.45 (bs, 2H).

(xxii) 6-(1,3-Benzodioxol-5-yl)-5-phenyl-1,2,4-triazin-3-amine

[1245] 6-(1,3-Benzodioxol-5-yl)-5-phenyl-1,2,4-triazin-3-amine (54 mg, 62%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and benzo[d][1,3]dioxol-5-ylboronic acid (57.0 mg, 0.344 mmol) according to the general procedure of Example 1.

[1246] HPLC purity: 100% (254 nm)

[1247] Mass spectroscopy: 293.2 (M+H).sup.+

[1248] .sup.1H NMR: (400 MHz, d6-DMSO) δ: 6.05 (s, 2H), 6.52 (dd, 1H), 6.83 (m, 1H), 6.87 (m, 1H), 7.32 (bs, 2H), 7.35-7.43 (m, 5H).

(xxiii) 3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)benzonitrile

[1249] 3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)benzonitrile (20 mg, 25%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3-cyanophenylboronic acid (50.5 mg, 0.344 mmol) according to the general procedure of Example 1.

[1250] HPLC purity: 96.0% (254 nm)

[1251] Mass spectroscopy: (ESI +ve) 274.2 (M+H).sup.+

[1252] .sup.1H NMR: (400 MHz, d-DMSO) δ: 7.30-7.35 (m, 4H), 7.52 (m, 1H), 7.52 (m, 1H), 7.54 (bs, 2H), 7.63 (m, 1H), 7.82 (m, 2H).

(xxiv) 6-(3,5-Dimethoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine

[1253] 6-(3,5-Dimethoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (55 mg, 60%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3,5-dimethoxyphenylboronic acid (62.5 mg, 0.344 mmol) according to the general procedure of Example 1.

[1254] HPLC purity: 100% (254 nm)

[1255] Mass spectroscopy: (ESI +ve) 309.2 (M+H).sup.+

[1256] .sup.1H NMR: (400 MHz, d6-DMSO) δ: 3.70 (s, 6H), 6.54 (m, 3H), 7.42-7.54 (m, 7H).

(xxv) 6-(3,5-Dimethylphenyl)-5-phenyl-1,2,4-triazin-3-amine

[1257] 6-(3,5-Dimethylphenyl)-5-phenyl-1,2,4-triazin-3-amine (54 mg, 65%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3,5-dimethylphenylboronic acid (51.5 mg, 0.344 mmol) according to the general procedure of Example 1.

[1258] HPLC purity: 100% (254 nm)

[1259] Mass spectroscopy: (ESI +ve) 277.2 (M+H).sup.+

[1260] .sup.1H NMR: (400 MHz, d6-DMSO) δ: 2.06 (s, 6H), 6.82 (m, 3H), 7.18-7.27 (m, 7H).

(xxvi) 6-(3,4-Dimethylphenyl)-5-phenyl-1,2,4-triazin-3-amine

[1261] 6-(3,4-Dimethylphenyl)-5-phenyl-1,2,4-triazin-3-amine (55 mg, 67%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3,4-dimethylphenylboronic acid (51.5 mg, 0.344 mmol) according to the general procedure of Example 1.

[1262] HPLC purity: 100% (254 nm)

[1263] Mass spectroscopy: (ESI +ve) 277.2 (M+H).sup.+

[1264] .sup.1H NMR: (400 MHz, d6-DMSO) δ: 2.15 (s, 31H), 2.17 (s, 3H), 6.88 (m, 1H), 7.02 (m, 1H), 7.23 (m, 1H), 7.32 (bs, 2H), 7.34 (m, 2H), 7.87-7.42 (m, 3H).

(xxvii) 6-[3-(Dimethylamino)phenyl]-5-phenyl-1,2,4-triazin-3-amine

[1265] 6-[3-(Dimethylamino)phenyl]-5-phenyl-1,2,4-triazin-3-amine (53 mg, 60%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3-(dimethylamino)phenylboronic acid (56.7 mg, 0.344 mmol) according to the general procedure of Example 1.

[1266] HPLC purity: 98.3% (254 nm)

[1267] Mass spectroscopy: (ESI +ve) 292.2 (M+H).sup.+

[1268] .sup.1H NMR: (400 MHz, d6-DMSO) δ: 2.77 (s, 6H), 6.58 (m, 1H), 6.67 (m, 2H), 7.09 (m, 1H). 7.32 (bs, 2H), 7.34 (m, 2H), 7.40 (m, 3H).

(xxviii) N-[3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]acetamide

[1269] N-[3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]acetamide (59 mg, 62%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3-acetamidophenylboronic acid (61.5 mg, 0.344 mmol) according to the general procedure of Example 1.

[1270] HPLC purity: 100% (254 nm)

[1271] Mass spectroscopy: (ESI +ve) 306.2 (M+H).sup.+

[1272] .sup.1H NMR: (400 MHz, d6-DMSO) δ: 1.95 (s, 3H), 6.70 (m, 1H), 7.07 (m, 1H), 7.25-7.35 (m, 6H), 7.52 (m, 2H), 7.64 (m, 1H), 9.89 (s, 1H).

(xxix) N-[3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]methanesulfonamide

[1273] N-[3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]methanesulfonamide (42 mg, 41%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (102 mg, 0.344 mmol) according to the general procedure of Example 1.

[1274] HPLC purity: 100% (254 nm)

[1275] Mass spectroscopy: (ESI +ve) 342.2 (M+H).sup.+

[1276] .sup.1H NMR: (400 MHz, d6-DMSO) δ: 2.79 (s, 3H), 7.02 (m, 1H), 7.36 (m, 1H), 7.26 (m, 2H). 7.35-7.48 (m, 7H), 9.78 (s, 1H).

(xxx) 6-(3-Chlorophenyl)-5-(2,4-difluorophenyl)-1,2,4-triazin-3-amine

[1277] 6-(3-Chlorophenyl)-5-(2,4-difluorophenyl)-1,2,4-triazin-3-amine (23 mg, 15%) was prepared from 6-bromo-5(2,4-difluorophenyl)-1,2,4-triazin-3-amine (0.13 g, 0.40 mmol) and 3-chlorophenylboronic acid (0.07 g, 0.40 mmol) according to the general procedure of Example 1.

[1278] HPLC purity: 98.7% (260 nm)

[1279] Mass spectroscopy: (ESI +ve) 318.9 [M+H].sup.+, 317.1 [M−H].sup.−.

[1280] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 5.64 (s, 2H), 6.75 (m, 1H), 7.01 (m, 1H), 7.20 (m, 2H), 7.32 (m, 1H), 7.48 (s, 1H), 7.54 (m, 1H).

(xxxi) 6-(3-Chlorophenyl)-5-(3-methoxyphenyl)-1,2,4-triazin-3-amine

[1281] 6-(3-Chlorophenyl)-5-(3-methoxyphenyl)-1,2,4-triazin-3-amine (18 mg 9%) was prepared from 6-bromo-5-(3-methoxyphenyl)-1,2,4-triazin-3-amine (0.18 g, 0.60 mmol) and 3-chlorophenylboronic acid (0.10 g, 0.60 mmol) according to the general procedure of Example 1.

[1282] HPLC purity: 88% (258 nm)

[1283] Mass spectroscopy: (ESI +ve) 313.0 [M+H].sup.+, 311.1 [M−H].sup.−.

[1284] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 3.72 (s, 3H), 6.53 (s, 2H), 7.04 (m, 3H), 7.23-7.30 (m, 3H), 7.37 (d, 1H), 7.49 (s, 1H).

(xxxii) 6-(3-Chlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine

[1285] 6-(3-Chlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (65.0 mg, 19%) was prepared from 6-bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (0.30 g, 1.11 mmol) and 3-chlorophenylboronic acid (0.19 g, 1.23 mmol) according to the general procedure of Example 1.

[1286] HPLC purity: 98% (261 nm)

[1287] Mass spectroscopy: (ESI +ve) 300.9 [M+H].sup.+.

[1288] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 5.47 (s, 2H), 7.03 (m, 2H), 7.19-7.26 (m, 3H), 7.33 (m, 1H), 7.47 (m, 2H), 7.53 (m, 1H).

(xxxiii) 6-(2-Methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine

[1289] 6-(2-Methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (108 mg, 48%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and 2-methoxyphenyl boronic acid (0.137 g, 0.90 mmol) according to the general procedure of Example 1.

[1290] HPLC purity: 99.28% (223 nm)

[1291] Mass spectroscopy: (ESI +ve) 278.9 [M+H].sup.+.

[1292] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 3.20 (s, 3H), 5.49 (s, 2H), 6.70 (t, 1H) 7.10 (m, 2H), 7.26 (m, 1H), 7.32-7.39 (m, 2H), 7.43 (m, 2H), 7.64 (dd, 1H).

(xxxiv) 6-(3-trifluoromethoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine

[1293] 6-(3-trifluoromethoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (170 mg, 25%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and 3-(trifluoromethoxy)phenyl boronic acid (0.44 g, 2.13 mmol) according to the general procedure of Example 1.

[1294] HPLC purity: 99% (262 nm)

[1295] Mass spectroscopy: (ESI +ve) 332.9 [M+H].sup.+

[1296] .sup.1H NMR: (400 MHz, CDCl3) δ: 5.46 (s, 2H), 7.19 (m, 1H), 7.25 (m, 1H) 7.36 (m, 3H), 7.43 (t, 4H).

(xxxv) 6-(1-benzofuran-5-yl)-5-phenyl-1,2,4-triazin-3-amine

[1297] 6-(1-benzofuran-5-yl)-5-phenyl-1,2,4-triazin-3-amine (225 mg, 47%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and benzofuran-5 boronic acid (0.32 g, 1.99 mmol) according to the general procedure of Example 1.

[1298] HPLC purity: 99.61% (245 nm)

[1299] Mass spectroscopy: (ESI +ve) 288.9 [M+H].sup.+

[1300] .sup.1H NMR: (400 MHz, DMSO) δ: 6.92 (m, 1H), 7.20 (m, 1H), 7.27 (m, 2H), 7.36 (m, 5H), 7.52 (d, 1H), 7.66 (d, 1H), 7.98 (d, 1H).

(xxxvi) 5-phenyl-6-[3-(propan-2-yl)phenyl]-1,2,4-triazin-3-amine

[1301] 5-phenyl-6-[3-(propan-2-yl)phenyl]-1,2,4-triazin-3-amine (110 mg, 33%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.3 g, 1.19 mmol) and 3-isopropyl phenyl boronic acid (0.215 g, 1.31 mmol) according to the general procedure of Example 1.

[1302] HPLC purity: 99.78% (262 nm)

[1303] Mass spectroscopy: (ESI +ve) 291.0 [M+H].sup.+

[1304] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 1.09 (d, 6H), 2.79 (m, 1H), 5.48 (bs, 2H), 7.19 (m, 2H), 7.31 (m, 4H), 7.44 (m, 3H).

(xxxvii) 6-(3,5-dichlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine

[1305] 6-(3,5-dichlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (0.11 g, 17.6%) was prepared from 6-Bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (0.5 g, 1.18 mmol) and 3,5-dichloro phenylboronic acid (0.47 mg, 2.4 mmol) according to the general procedure of Example 1.

[1306] HPLC purity: 97.46% (225 nm)

[1307] Mass spectroscopy: (ESI +ve) 334.9 [M].sup.+.

[1308] .sup.1H NMR: (400 MHz, DMSO) δ: 7.24 (m, 2H), 7.34 (m, 2H) 7.45 (m, 2H), 7.58 (m, 3H).

(xxxviii) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-(propan-2-yloxy)phenol

[1309] 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-(propan-2-yloxy)phenol (0.450 g, 18%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (1.9 g, 7.52 mmol) and 3-isopropoxy-4-hydroxyphenylboronic acid pinacol ester (2.5 g, 9.02 mmol) according to the general procedure of Example 1.

[1310] HPLC purity: 94.14% (290 nm)

[1311] Mass spectroscopy: (ESI +ve) 323.1 [M+H].sup.+ (ESI −ve) 321.1 [M+H].sup.+.

[1312] .sup.1H NMR: (400 MHz, DMSO) δ: 1.04 (d, 6H), 4.20 (m, 1H), 6.68 (m, 1H), 6.70 (m, 1H), 6.84 (m, 1H), 7.26 (bs. 2H), 7.32-7.44 (m, 5H), 9.01 (s, 1H).

[1313] The compounds in the following table were prepared using the general procedure outlined for Example 1, by reacting the corresponding starting materials at 140° C. for 1 hour.

TABLE-US-00006 No. Product (yield) Prepared From LCMS NMR (xxxix) 6-(3,5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: bis(trifluoromethyl)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 7.35-7.43 (m, 4H), nyl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 385.3 (M + H).sup.+ 7.44-7.50 (m, 1H), triazin-3-amine (50.2 and 3,5- (ES.sup.+); 383.5 (M − H).sup.− 7.68 (s, 2H), 7.94 (s, mg, 0.131 mmol, bis(trifluoromethyl)phe- (ES.sup.−), at 4.89 min, 2H), 8.06 (s, 1H). 36.4%) nylboronic acid (106 100% (method B). mg, 0.412 mmol) (xl) 4-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)-2- 1,2,4-triazin-3-amine spectroscopy: m/z 3.55 (s, 3H), 6.65- methoxyphenol (42.5 (90 mg, 0.358 mmol) 295.2 (M + H).sup.+ 6.76 (m, 2H), 6.85 (d, mg, 0.139 mmol, and -methoxy-4- (ES.sup.+); 293.4 (M − H).sup.− J 1.8, 1H), 7.28 (s, 38.7%) (4,4,5,5-tetramethyl- (ES.sup.−), at 2.70 min, 2H), 7.33-7.45 (m, 1,3,2-dioxaborolan-2- 96.0% (method B). 5H), 9.18 (s, 1H). yl)phenol (103 mg, 0.412 mmol) (xli) 4-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)- 1,2,4-triazin-3-amine spectroscopy: m/z 2.06 (s, 6H), 6.87 (s, 2,6-dimethylphenol (90 mg, 0.358 mmol) 293.2 (M + H).sup.+ 2H), 7.31-7.64 (m, (41.3 mg, 0.141 and 2,6-dimethyl-4- (ES.sup.+); 291.4 (M − H).sup.− 7H), 8.46 (s, 1H). mmol, 39.4%) (4,4,5,5-tetramethyl- (ES.sup.−), at 3.57 min, 1,3,2-dioxaborolan-2- 100% (method B). yl)phenol (102 mg, 0.412 mmol) (xlii) 4-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)-2- 1,2,4-triazin-3-amine spectroscopy: m/z 6.87 (d, J 8.4, 1H), chlorophenol (26.8 (90 mg, 0.358 mmol) (Cl) 299.2/301.2 7.03 (dd, J 8.4, 2.2, mg, 0.085 mmol, and 3-chloro-4- (M + H).sup.+ (ES.sup.+); 1H), 7.31 (d, J 2.2, 23.78%) hydroxyphenylboronic 297.4/299.4 (M − H).sup.− 1H), 7.33-7.47 (m, acid (64.9 mg, (ES.sup.−), at 2.15 min, 7H), 10.38 (s, 1H). 0.376 mmol) 97.1% (method B). (xliii) 6-(2-chloropyridin-4- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: yl)-5-phenyl-1,2,4- 1,2,4-triazin-3-amine spectroscopy: m/z 7.28 (dd, J 5.2, 1.5, triazin-3-amine (22.5 (90 mg, 0.358 mmol) (Cl) 284.1/286.1 1H), 7.38-7.53 (m, mg, 0.079 mmol, and 2-chloropyridin- (M + H).sup.+ (ES.sup.+); 6H), 7.74 (s, 2H), 22.12%) 4-ylboronic acid 282.3/284.3 (M − H).sup.− 8.33 (dd, J 5.2, 0.6, (59.2 mg, 0.376 (ES.sup.−), at 3.55 min, 1H). mmol) 100% (method B). (xliv) 6-(3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (methylsulfonyl)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 3.10 (s, 3H), 7.33- nyl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 327.2 (M + H).sup.+ 7.48 (m, 5H), 7.50- triazin-3-amine (78.8 and 3- (ES.sup.+); 325.4 (M − H).sup.− 7.68 (m, 4H), 7.83- mg, 0.241 mmol, (methylsulfonyl)phe- (ES.sup.−), at 3.12 min, 7.91 (m, 2H). 67.4%) nylboronic acid (82 100% (method B). mg, 0.412 mmol) (xlv) 6-(3,5-dichloro-4- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: methoxyphenyl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 3.83 (s, 3H), 7.37- phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) (2Cl) 7.50 (m, 7H), 7.55 (s, 3-amine (52 mg, and 3,5-dichloro-4- 347.2/349.2/351.2 2H). 0.147 mmol, 41.1%) methoxyphenylboronic (M + H).sup.+ (ES.sup.+); acid (83 mg, 0.376 345.3/347.3/349.4 mmol) (M − H).sup.− (ES.sup.−), at 4.57 min, 91.0% (method B). (xlvi) 6-(4-methoxy-3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 3.88 (s, 3H), 7.21 (d, nyl)-5-phenyl-1,2,4- (75 mg, 0.299 mmol) 347.2 (M + H).sup.+ J 8.6, 1H), 7.33- triazin-3-amine (53.4 and 4-methoxy-3- (ES.sup.+); 345.4 (M − H).sup.− 7.50 (m, 7H), 7.51- mg, 0.154 mmol, (trifluoromethyl)phe- (ES.sup.−), at 4.25 min, 7.59 (m, 2H). 51.6%) nylboronic acid (76 100% (method B). mg, 0.344 mmol) (xlvii) 6-(3-chloro-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (dimethylamino)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 2.75 (s, 6H), 6.47- nyl)-5-phenyl-1,2.4- (90 mg, 0.358 mmol) (Cl) 326.3/328.2 6.53 (m, 1H), 6.61- triazin-3-amine (68.3 and 3-chloro-N,N- (M + H).sup.+ (ES.sup.+): 6.68 (m, 2H), 7.30- mg, 0.204 mmol, dimethyl-5-(4,4,5,5- 324.4/326.4 (M − H).sup.− 7.54 (m, 7H). 57.0%) tetramethyl-1,3,2- (ES.sup.−), at 4.53 min, dioxaborolan-2- 100% (method B). yl)aniline (106 mg, 0.376 mmol) (xlviii) 3-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 7.36-7.42 (m, 4H), (trifluoromethyl)benzo- (90 mg, 0.358 mmol) 342.9 (M + H).sup.+ 7.43-7.51 (m, 1H), nitrile (47.5 mg, and 3-(4,4,5,5- (ES.sup.+); 341.0 (M − H).sup.− 7.69 (s, 2H), 7.90 (s, 0.137 mmol, 38.2%) tetramethyl-1,3,2- (ES.sup.−), at 4.25 min, 1H), 8.09(s, 1H), dioxaborolan-2-yl)-5- 98.4% (method B). 8.31 (s, 1H). (trifluoromethyl)benzo- nitrile (122 mg, 0.412 mmol) (xlix) 4-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)- 1,2,4-triazin-3-amine spectroseopy: m/z 2.37 (s, 6H), 7.22 (s, 2,6- (90 mg, 0.358 mmol) 302.2 (M + H).sup.+ 2H), 7.35-7.42 (m, dimethylbenzonitrile and 2,6-dimethyl-4- (ES.sup.+); 300.4 (M − H).sup.− 4H), 7.43-7.49 (m, (72.4 mg, 0.233 (4,4,5,5-tetramethyl- (ES.sup.−), at 4.14 min, 1H), 7.57 (s, 2H). mmol, 65.0%) 1,3,2-dioxaborolan-2- 100% (method B). yl)benzonitrile (106 mg, 0.412 mmol) (l) 6-(3-chloro-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 7.35-7.43 (m, 4H), nyl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 351.9 (M + H).sup.+ 7.44-7.49 (m, 1H), triazin-3-amine (42.5 and 2-(3-chloro-5- (ES.sup.+); 350.0 (M − H).sup.− 7.55 (s, 1H), 7.63 (s, mg, 0.117 mmol, (trifluoromethyl)phe- (ES.sup.−), at 4.80 min, 2H), 7.72 (s, 1H), 32.6%) nyl)-4,4,5,5- 96.4% (method B). 7.82 (s, 1H). tetramethyl-1,3,2- dioxaborolane (115 mg, 0.376 mmol) (li) 6-(3-chloro-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: methylphenyl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 2.24 (s, 3H), 7.07- phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) (Cl) 297.1/299.3 7.12 (m, 1H), 7.13- 3-amine (65.1 mg, and 3-chloro-5- (M + H).sup.+ (ES.sup.+); 7.17 (m, 1H), 7.21- 0.219 mmol, 61.2%) methylphenylboronic 295.3/297.3 (M − H).sup.− 7.25 (m, 1H), 7.33- acid (64.1 mg, 0.376 (ES.sup.−), at 4.55 min, 7.57 (m, 7H). mmol) 100% (method B). (lii) 6-(3-(methylthio)-5- from 6-bromo-5- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe- phenyl-1,2,4-triazin- spectroscopy: m/z 2.33 (s, 3H), 7.35- nyl)-5-phenyl-1,2,4- 3-amine (90 mg, 363.2 (M + H).sup.+ 7.43 (m, 6H), 7.43- triazin-3-amine (66 0.358 mmol) and 3- (ES.sup.+); 361.4 (M − H).sup.− 7.47 (m, 1H), 7.57 (s, mg, 0.181 mmol, (methylthio)-5- (ES.sup.−), at 4.75 min, 2H), 7.49 (s, 1H). 50.5%) (trifluoromethyl)phe- 99.4% (method B). nylboronic acid (97 mg, 0.412 mmol) (liii) 6-(3-methoxy-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 3.71 (s, 3H), 7.14- nyl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 347.2 (M + H).sup.+ 7.22 (m, 3H), 7.35- triazin-3-amine (62.9 and 3-methoxy-5- (ES.sup.+); 345.4 (M − H).sup.− 7.42 (m, 4H), 7.42- mg, 0.179 mmol, (trifluoromethyl)phe- (ES.sup.−), at 4.52 min, 7.47 (m, 1H), 7.55 (s, 49.9%) nylboronic acid (91 99.5% (method B). 2H). mg, 0.412 mmol) (liv) 6-(3-ethoxy-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 1.23 (t, J 7.0, 3H), nyl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 361.2 (M + H).sup.+ 3.97 (q, J 7.0, 2H), triazin-3-amine (76.4 and 3-ethoxy-5- (ES.sup.+); 359.5 (M − H).sup.− 7.12-7.15 (m, 1H), mg, 0.211 mmol, (trifluoromethyl)phe- (ES.sup.−), at 4.74 min, 7.15-7.17 (m, 1H), 58.8%) nylboronic acid (96 99.4% (method B). 7.18-7.21 (m, 1H), mg, 0.412 mmol) 7.34-7.48 (m, 5H), 7.54 (s, 2H). (lv) 6-(3-tert-butyl-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: methylphenyl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 1.03 (s, 9H), 2.31 (s, phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) 319.5 (M + H).sup.+ 3H), 6.80-6.85 (m, 3-amine (80 mg, and with 3-tert-butyl- (ES.sup.+); 317.5 (M − H).sup.− 1H), 7.11-7.15 (m, 0.249 mmol, 69.5%) 5- (ES.sup.−), at 4.99 min, 1H), 7.24-7.28 (m, methylphenylboronic 99.1% (method B). 1H), 7.30-7.44 (m, acid (79 mg, 0.412 7H). mmol) (lvi) 6-(2-chloro-6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: methylpyridin-4-yl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 2.39 (s, 3H), 7.08- phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) (Cl) 298.1/300.1 7.13 (m, 1H), 7.24- 3-amine (52.5 mg, and 2-chloro-6- (M + H).sup.+ (ES.sup.+): 7.30 (m, 1H), 7.39- 0.170 mmol, 47.3%) methyl-4-(4,4,5,5- 296.3/298.3 (M − H).sup.− 7.45 (m, 4H), 7.46- tetramethyl-1,3,2- (ES.sup.−), at 3.73 min, 7.53 (m, 1H), 7.71 (s, dioxaborolan-2- 99.6% (method B). 2H). yl)pyridine (100 mg, 0.394 mmol) (lvii) 4-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)-2- 1,2,4-triazin-3-amine spectroscopy: m/z 7.36-7.44 (m, 5H), chlorobenzonitrile (90 mg, 0.358 mmol) (Cl) 308.1/310.1 7.44-7.50 (m, 1H), (29 mg, 0.092 mmol, and 3-chloro-4- (M + H).sup.+ (ES.sup.+); 7.69 (s, 2H), 7.73 (d, 25.7%) cyanophenylboronic 306.3/308.3 (M − H).sup.− J 1.3, 1H), 7.91 (d, J acid (71.5 mg, 0.394 (ES.sup.−), at 4.02 min, 8.2, 1H). mmol) 97.9% (method B). (lviii) 6-(3-ethylphenyl)-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: phenyl-1,2,4-triazin- 1,2,4-triazin-3-amine spectroscopy: m/z 1.03 (t, J 7.6, 3H), 3-amine (70 mg, (90 mg, 0.358 mmol) 277.2 (M + H).sup.+ 2.51 (q, J 7.6, 2H), 0.252 mmol, 70.3%) and 3- (ES.sup.+); 275.4 (M − H).sup.− 7.12-7.18 (m, 3H), ethylphenylboronic (ES.sup.−), at 4.49 min, 7.20-7.26 (m, 1H), acid (61.8 mg, 0.412 99.5% (method B). 7.31-7.45 (m, 7H). mmol) (lix) 6-(2-methoxy-6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethyl)pyridin- 1,2,4-triazin-3-amine spectroscopy: m/z 3.86 (s, 3H), 7.00- 4-yl)-5-phenyl- (90 mg, 0.358 mmol) 348.2 (M + H).sup.+ 7.04 (m, 1H), 7.34 (d, 1,2,4-triazin-3-amine and 2-methoxy-4- (ES.sup.+); 346.4 (M − H).sup.− J 1.1, 1H), 7.38- (61.6 mg, 0.176 (4,4,5,5-tetramethyl- (ES.sup.−), at 4.47 min, 7.46 (m, 4H), 7.46- mmol, 49.2%) 1,3,2-dioxaborolan-2- 99.4% (method B). 7.52 (m, 1H), 7.75 (s, yl)-6- 2H). (trifluoromethyl)pyri- dine (125 mg, 0.412 mmol) (lx) 6-(3-methyl-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethoxy)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 2.32 (s, 3H), 6.85- nyl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 347.2 (M + H).sup.+ 6.91 (m, 1H), 7.12- triazin-3-amine (41 and 4,4,5,5- (ES.sup.+); 345.4 (M − H).sup.− 7.18 (m, 1H), 7.32- mg, 0.116 mmol, tetramethyl-2-(3- (ES.sup.−), at 4.72 min, 7.41 (m, 5H), 7.41- 32.3%) methyl-5- 97.7% (method B). 7.47 (m, 1H), 7.51 (s, (trifluoromethoxy)phe- 2H). nyl)-1,3,2- dioxaborolane (125 mg, 0.412 mmol) (lxi) 6-(3-(1,3-dioxolan-2- from 6-bromo-5- Mass (400 MHz, DMSO) δ: yl)-5- phenyl-1,2,4-triazin- spectroscopy: m/z 3.92 (s, 4H), 5.81 (s, (trifluoromethyl)phe- 3-amine (90 mg, 389.3 (M + H).sup.+ 1H), 7.34-7.41 (m, nyl)-5-phenyl-1,2,4- 0.358 mmol) and 3- (ES.sup.+); 387.5 (M − H).sup.− 4H), 7.41-7.48 (m, triazin-3-amine (76 (1,3-dioxolan-2-yl)-5- (ES.sup.−), at 4.32 min, 1H), 7.57 (s, 2H), mg, 0.194 mmol, (trifluoromethyl)phe- 95.3% (method B). 7.60 (s, 1H), 7.68 (s, 54.2%) nylboronic acid (108 1H), 7.73 (s, 1H). mg, 0.412 mmol) (lxii) 5-phenyl-6-(3-(2,2,2- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: trifluoroethoxy)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 4.69 (q, J 8.9, 2H), nyl)-1,2,4-triazin-3- (90 mg, 0.358 mmol) 347.2 (M + H).sup.+ 6.87-6.93 (m, 1H), amine (86 mg, 0.246 and 3-(2,2,2- (ES.sup.+); 345.4 (M − H).sup.− 7.02 (ddd, J 8.3, 2.7, mmol, 68.6%) trifluoroethoxy)phenyl- (ES.sup.−), at 4.30 min, 0.8, 1H), 7.07-7.12 boronic acid (91 mg, 99.0% (method B). (m, 1H), 7.25 (t, J 0.412 mmol) 8.0, 1H), 7.31-7.52 (m, 7H). (lxiii) 6-(3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (methoxymethyl)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 3.16 (s, 3H), 4.35 (s, nyl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 293.0 (M + H).sup.+ 2H), 7.16-7.22 (m, triazin-3-amine (76 and 3- (ES.sup.+); 291.3 (M − H).sup.− 1H), 7.25-7.30 (m, mg, 0.256 mmol, (methoxymethyl)phe- (ES.sup.−), at 3.85 min, 2H), 7.30-7.37 (m, 71.4%) nylboronic acid (68.4 98.5% (method B). 3H), 7.36-7.49 (m, mg, 0.412 mmol) 5H). (lxiv) 5-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)-1- 1,2,4-triazin-3-amine spectroscopy: m/z 3.44 (s, 3H), 6.23 (d, methylpyridin-2(1H)- (90 mg, 0.358 mmol) 280.0 (M + H).sup.+ J 9.4, 1H), 7.03 (dd, J one (50 mg, 0.177 and 1-methyl-5- (ES.sup.+); 278.2 (M − H).sup.− 9.4, 2.6, 1H), 7.33- mmol, 49.2%) (4,4,5,5-tetramethyl- (ES.sup.−), at 2.73 min, 7.50 (m, 5H), 7.51- 1,3,2-dioxaborolan-2- 98.6% (method B). 7.57 (m, 2H), 7.97 (d, yl)pyridin-2(1H)-one J 2.5, 1H). (97 mg, 0.412 mmol) (lxv) 6-(3-methyl-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 2.33 (s, 3H), 7.32 (s, nyl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 331.1 (M + H).sup.+ 1H), 7.34-7.41 (m, triazin-3-amine (79 and 3-methyl-5- (ES.sup.+); 329.3 (M − H).sup.− 4H), 7.41-7.47 (m, mg, 0.239 mmol, (trifluoromethyl)phe- (ES.sup.−), at 4.62 min, 1H), 7.48-7.60 (m, 66.6%) nylboronic acid (84 99.8% (method B). 4H). mg, 0.412 mmol) (lxvi) 6-(2-methoxypyridin- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 4-yl)-5-phenyl-1,2,4- 1,2,4-triazin-3-aimine spectroscopy: m/z 3.81 (s, 3H), 6.75 triazin-3-amine (39 (90 mg, 0.358 mmol) 280.1 (M + H).sup.+ (dd, J 1.4, 0.7, 1H), mg, 39%) and 2-methoxy-4- (ES.sup.+); 278.4 (M − H).sup.− 6.88 (dd, J 5.3, 1.5, (4,4,5,5-tetramethyl- (ES.sup.−), at 3.60 min, 1H), 7.34-7.51 (m, 1,3,2-dioxaborolan-2- 99.4% (method B). 5H), 7.61 (s, 2H), yl)pyridine (97 mg, 8.08 (dd, J 5.3, 0.7, 0.412 mmol) 1H). (lxvii) 1-(3-(3-amino-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: phenyl-1,2,4-triazin- 1,2,4-triazin-3-amine spectroscopy; m/z 2.46 (s, 3H), 7.32- 6-yl)phenyl)ethanone (90 mg, 0.358 mmol) 291.1 (M + H).sup.+ 7.52 (m, 8H), 7.52- (71 mg, 0.243 mmol, and 3- (ES.sup.+); 289.3 (M − H).sup.− 7.57 (m, 1H), 7.87- 67.8%) acetylphenylboronic (ES.sup.−), at 3.62 min, 7.93 (m, 1H), 7.93- acid (67.6 mg, 0.412 99.4% (method B). 7.98 (m, 1H). mmol) (lxviii) 4-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6- 1,2,4-triazin-3-amine spectroscopy: m/z 7.31-7.46 (m, 8H), yl)benzamide (73 (90 mg, 0.358 mmol) 292.2 (M + H).sup.+ 7.48 (s, 2H), 7.81 (d, mg, 0.243 mmol, and 4- (ES.sup.+); 290.4 (M − H).sup.− J 8.5, 2H), 7.98 (s, 67.7%) carbamoylphenylbo- (ES.sup.−), at 2.93 min, 1H). ronic acid (68.0 mg, 96.9% (method B). 0.412 mmol) (lxix) 6-(4-fluoro-3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 7.32-7.51 (m, 6H), nyl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 335.2 (M + H).sup.+ 7.55 (s, 2H), 7.63- triazin-3-amine (83 and 2-(4-fluoro-3- (ES.sup.+); 333.4 (M − H).sup.− 7.68 (m, 1H), 7.70 mg, 0.244 mmol, (trifluoromethyl)phe- (ES.sup.−), at 4.42 min, (dd, J 7.0, 2.1, 1H). 68.0%) nyl)-4,4,5,5- 98.2% (method B). tetramethyl-1,3,2- dioxaborolane (120 mg, 0.412 mmol) (lxx) 6-(4-fluoro-3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: methylphenyl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 2.19 (s, 3H), 7.00- phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) 281.1 (M + H).sup.+ 7.09 (m, 2H), 7.32- 3-amine (72 mg, and 4-fluoro-3- (ES.sup.+); 279.3 (M − H).sup.− 7.46 (m, 8H). 0.257 mmol, 71.7%) methylphenylboronic (ES.sup.−), at 4.32 min, acid (63.5 mg, 0.412 100% (method B). mmol) (lxxi) 6-(3-bromo-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: chlorophenyl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 7.36-7.38 (m, 1H), phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) (Br) 7.39-7.44 (m, 4H), 3-amine (30 mg, and 2-(3-bromo-5- 361.2/363.1/365.1 7.44-7.50 (m, 2H), 0.083 mmol, 23.14%) chlorophenyl)- (M + H).sup.+ (ES.sup.+); 7.59 (s, 2H), 7.69 (t, J 4,4,5,5-tetramethyl- 359.3/361.3/363.3 1.9, 1H). 1,3,2-dioxaborolane (M − H).sup.− (ES.sup.−), at (116 mg, 0.366 5.07 min, 100% mmol) (method B). (lxxii) 6-(naphthalen-2-yl)- from 6-bromo-5- Mass (400 MHz, DMSO) δ: 5-phenyl-1,2,4- phenyl-1,2,4-triazin- spectroscopy: m/z 7.28-7.36 (m, 3H), triazin-3-amine (83 3-amine (90 mg, 299.2 (M + H).sup.+ 7.37-7.48 (m, 5H), mg, 0.278 mmol, 77%) 0.358 mmol) and (ES.sup.+), at 4.67 min, 7.48-7.56 (m, 2H), naphthalen-2- 99.8% (method B). 7.81 (d, J 8.7, 1H), ylboronic acid (70.9 7.83-7.92 (m, 2H), mg, 0.412 mmol) 8.02 (s, 1H). (lxxiii) 5-phenyl-6-m-tolyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-3-amine 1,2,4-triazin-3-amine spectroscopy: m/z 2.26 (s, 3H), 6.97- (73.4 mg, 0.278 (90 mg, 0.358 mmol) 263.2 (M + H).sup.+ 7.02 (m, 1H), 7.11- mmol, 78%) and m-tolylboronic (ES.sup.+); 261.3 (M − H).sup.− 7.20 (m, 2H), 7.26 (s, acid (56.0 mg, 0.412 (ES.sup.−), at 4.43 min, 1H), 7.30-7.45 (m, mmol) 99.4% (method B). 7H). (lxxiv) 5-phenyl-6-(pyridin- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 4-yl)-1,2,4-triazin-3- 1,2,4-triazin-3-amine spectroscopy: m/z 7.32 (dd, J 4.4, 1.7, amine (16 mg, 0.064 (90 mg, 0.358 mmol) 250.2 (M + H).sup.+ 2H), 7.34-7.43 (m, mmol, 17.78%) and pyridin-4- (ES.sup.+); 248.3 (M − H).sup.− 4H), 7.43-7.50 (m, ylboronic acid (50.7 (ES.sup.−), at 3.34 min, 1H), 7.63 (s, 2H), mg, 0.412 mmol) 99.3% (method B). 8.51 (dd, J 4.5, 1.6, 2H). (lxxv) 4-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6- 1,2,4-triazin-3-amine spectroscopy: m/z 6.69 (d, J 8.7, 2H), yl)phenol (21 mg, (90 mg, 0.358 mmol) 265.1 (M + H).sup.+ 7.12 (d, J 8.6, 2H), 0.078 mmol, 21.81%) and 4-(4,4,5,5- (ES.sup.+); 263.4 (M − H).sup.− 7.26 (s, 2H), 7.31- tetramethyl-1,3,2- (ES.sup.−), at 2.77 min, 7.44 (m, 5H), 9.59 (s, dioxaborolan-2- 98.4% (method B). 1H). yl)phenol (91 mg, 0.412 mmol) (lxxvi) 6-(2,6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: dimethoxypyridin-4- 1,2,4-triazin-3-amine spectroscopy: m/z 3.79 (s, 6H), 6.29 (s, yl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 310.2 (M + H).sup.+ 2H), 7.35-7.49 (m, triazin-3-amine (61 and 2,6-dimethoxy-4- (ES.sup.+); 308.4 (M − H).sup.− 5H), 7.58 (s, 2H). mg, 0.196 mmol, (4,4,5,5-tetramethyl- (ES.sup.−), at 4.27 min, 54.8%) 1,3,2-dioxaborolan-2- 99.6% (method B). yl)pyridine (109 mg, 0.412 mmol) (lxxvii) 6-(2,6- from 6-bromo-5- Mass (400 MHz, DMSO) δ: dimethylpyridin-4-yl)- phenyl-1,2,4-triazin- spectroscopy: m/z 2.33 (s, 6H), 6.97 (s, 5-phenyl-1,2,4- 3-amine (90 mg, 278.2 (M + H).sup.+ 2H), 7.35-7.43 (m, triazin-3-amine (44 0.358 mmol) and 2,6- (ES.sup.+); 276.4 (M − H).sup.− 4H), 7.43-7.50 (m, mg, 0.154 mmol, dimethyl-4-(4,4,5,5- (ES.sup.−), at 3.77 min, 1H), 7.58 (s, 2H). 42.8%) tetramethyl-1,3,2- 96.8% (method B). dioxaborolan-2- yl)pyridine (96 mg, 0.412 mmol) (lxxviii) 5-phenyl-6-(2- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethyl)pyridin- 1,2,4-triazin-3-amine spectroscopy: m/z 7.37-7.45 (m, 4H), 4-yl)-1,2,4-triazin- (90 mg, 0.358 mmol) 318.2 (M + H).sup.+ 7.46-7.53 (m, 1H), 3-amine (31 mg, and 2- (ES.sup.+); 316.4 (M − H).sup.− 7.63 (dd, J 5.0, 1.2, 0.098 mmol, 27.3%) (trifluoromethyl)pyridin- (ES.sup.−), at 4.03 min, 1H), 7.75 (s, 1H), 4-ylboronic acid 100% (method B). 7.77 (s, 2H), 8.70 (d, (79 mg, 0.412 mmol) J 5.1, 1H). (lxxix) 6-(2- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: cyclopropylpyridin-4- 1,2,4-triazin-3-amine spectroscopy: m/z 0.76-0.83 (m, 2H), yl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) 290.1 (M + H).sup.+ 0.87-0.93 (m, 2H), triazin-3-amine (61 and 2-cyclopropyl-4- (ES.sup.+); 288.4 (M − H).sup.− 1.96-2.06 (m, 1H), mg, 0.206 mmol, (4,4,5,5-tetramethyl- (ES.sup.−), at 3.92 min, 6.97 (dd, J 5.1, 1.7, 57.3%) 1,3,2-dioxaborolan-2- 97.5% (method B). 1H), 7.25 (dd, J 1.6, yl)pyridine (101 mg, 0.8, 1H), 7.35-7.44 0.412 mmol) (m, 4H), 7.44-7.51 (m, 1H), 7.60 (s, 2H), 8.28 (dd, J 5.1, 0.6, 1H). (lxxx) 5-phenyl-6-(2,2,6,6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: tetramethyl-3,6- 1,2,4-triazin-3-amine spectroscopy: m/z 1.01 (s, 6H), 1.16 (s, dihydro-2H-pyran-4- (90 mg, 0.358 mmol) 311.2 (M + H).sup.+ 6H), 2.28 (d, J 1.3, yl)-1,2,4-triazin-3- and 4,4,5,5- (ES.sup.+); 309.4 (M − H).sup.− 2H), 5.46 (t, J 1.4, amine (85 mg, 0.269 tetramethyl-2- (ES.sup.−), at 4.40 min, 1H), 7.29 (s, 2H), mmol, 75%) (2,2,6,6-tetramethyl- 98.2% (method B). 7.43-7.50 (m, 3H), 3,6-dihydro-2H- 7.56-7.61 (m, 2H). pyran-4-yl)-1,3,2- dioxaborolane (110 mg, 0.412 mmol) (lxxxi) 6-(5-chloro-2-fluoro- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 3-methylphenyl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 2.07 (d, J 1.9, 3H), phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) (Cl) 315.8/317.8 7.33-7.47 (m, 6H), 3-amine (10 mg, and 5-chloro-2- (M + H).sup.+ (ES.sup.+), at 7.50 (dd, J 5.9, 2.8, 0.031 mmol, 8.64%) fluoro-3- 4.67 min, 97.5% 1H), 7.60 (s, 2H). methylphenylboronic (method B). acid (78 mg, 0.412 mmol) (lxxxii) 6-(2,6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: dichloropyridin-4-yl)- 1,2,4-triazin-3-amine spectroscopy: m/z 7.41-7.48 (m, 6H), 5-phenyl-1,2,4- (250 mg, 0.996 (2 Cl) 7.48-7.55 (m, 1H), triazin-3-amine (7 mmol) and 2,6- 318.0/320.1/322.1 7.85 (s, 2H). mg, 0.022 mmol, dichloro-4-(4,4,5,5- (M + H).sup.+ (ES.sup.+); 2.205%) tetramethyl-1,3,2- 316.3/318.2/320.2 dioxaborolan-2- (M − H).sup.− (ES.sup.−), at yl)pyridine (286 mg, 4.34 min, 94.8% 1.045 mmol) (method B). (lxxxiii) 6-(3-bromo-5- 6-iodo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethoxy)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 7.14-7.19 (m, 1H), nyl)-5-phenyl-1,2,4- (100 mg, 0.335 (Br) 411.8/413.8 7.36-7.42 (m, 4H), triazin-3-amine (23 mmol) and 3-bromo- (M + H).sup.+ (ES.sup.+): 7.42-7.49 (m, 1H), mg, 0.055 mmol, 5- 410.0/412.0 (M − H).sup.− 7.57-7.66 (m, 2H), 16.47%) (trifluoromethoxy)phe- (ES.sup.−), at 5.15 min, 7.63-7.66 (m, 1H), nylboronic acid (119 98.8% (method B). 7.67-7.70 (m, 1H). mg, 0.419 mmol) (lxxxiv) 4-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)-2- 1,2,4-triazin-3-amine spectroscopy: m/z 3.58 (s, 3H), 6.80 (d, chloro-6- (90 mg, 0.358 mmol) (Cl) 329.0/331.1 J 2.0, 1H), 6.92 (d, J methoxyphenol (72 and 2-chloro-6- (M + H).sup.+ (ES.sup.+); 2.0, 1H), 7.34-7.47 mg, 0.215 mmol, methoxy-4-(4,4,5,5- 327.2/329.0 (M − H).sup.− (m, 7H), 9.62 (s, 1H). 28.4%) tetramethyl-1,3,2- (ES.sup.−), at 2.61 min, dioxaborolan-2- 98.2% (method B). yl)phenol (248 mg, 0.870 mmol) (lxxxv) 6-(3,5-dichloro-4- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: ethoxyphenyl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 1.36 (t, J 7.0, 3H), phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) (2 Cl) 361.8/363.9 4.05 (q, J 7.0, 2H), 3-amine (81 mg, and 2-(3,5-dichloro- (M + H).sup.+ (ES.sup.+); 7.36-7.50 (m, 7H), 0.214 mmol, 59.8%) 4-ethoxyphenyl)- 360.1/362.1 (M − H).sup.− 7.55 (s, 2H). 4,4,5,5-tetramethyl- (ES.sup.−), at 5.02 min, 1,3,2-dioxaborolane 95.6% (method B). (131 mg, 0.412 mmol) (lxxxvi) 6-(6-amino-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethyl)pyridin- 1,2,4-triazin-3-amine spectroscopy: m/z 6.66 (s, 2H), 7.32- 3-yl)-5-phenyl- (90 mg, 0.358 mmol) 333.7 (M + H).sup.+ 7.50 (m, 7H), 7.62- 1,2,4-triazin-3-amine and 5-(4,4,5,5- (ES.sup.+); 331.8 (M − H).sup.− 7.67 (m, 1H), 8.01- (30 mg, 0.089 mmol, tetramethyl-1,3,2- (ES.sup.−), at 3.80 min, 8.09 (m, 1H). 24.78%) dioxaborolan-2-yl)-3- 98.4% (method B). (trifluoromethyl)pyridin- 2-amine (119 mg, 0.412 mmol) (lxxxvii) 4-(3-amino-5-(3- 6-bromo-5-(3- Mass (400 MHz, DMSO) δ: fluorophenyl)-1,2,4- fluorophenyl)-1,2,4- spectroscopy: m/z 2.39 (s, 6H), 7.11- triazin-6-yl)-2,6- triazin-3-amine (90 320.9 (M + H).sup.+ 7.17 (m, 1H), 7.25 (s, dimethylbenzonitrile mg, 0.334 mmol) (ES.sup.+); 319.1 (M − H).sup.− 2H), 7.26-7.35 (m, (70 mg, 0.219 mmol, and 2,6-dimethyl-4- (ES.sup.−), at 4.37 min, 2H), 7.37-7.44 (m, 65.5%) (4,4,5,5-tetramethyl- 99.9% (method B). 1H), 7.64 (s, 2H). 1,3,2-dioxaborolan-2- yl)benzonitrile (99 mg, 0.385 mmol) (lxxxviii) 6-(3-chloro-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe- 1,2,4-triazin-3-amine spectroscopy: m/z 7.15-7.21 (m, 1H), nyl)-5-(3- (90 mg, 0.358 mmol) (Cl) 369.8/371.9 7.25-7.36 (m, 2H), fluorophenyl)-1,2,4- and 2-(3-chloro-5- (M + H).sup.+ (ES.sup.+); 7.39-7.46 (m, 1H), triazin-3-amine (54 (trifluoromethyl)phe- 368.0/370.0 (M − H).sup.− 7.55-7.60 (m, 1H), mg, 0.141 mmol, nyl)-4,4,5,5- (ES.sup.−), at 4.99 min, 7.70 (s, 2H), 7.73- 42.1%) tetramethyl-1,3,2- 96.1% (method B). 7.77 (m, 1H), 7.84- dioxaborolane (118 7.88 (m, 1H). mg, 0.385 mmol) (lxxxix) 6-(2-chloropyridin-4- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: yl)-5-(3- 1,2,4-triazin-3-amine spectroscopy: m/z 7.16-7.23 (m, 1H), fluorophenyl)-1,2,4- (90 mg, 0.358 mmol) (Cl) 302.8/304.8 7.27-7.38 (m, 3H), triazin-3-amine (28 and 2-chloro-4- (M + H).sup.+ (ES.sup.+); 7.41-7.48 (m, 1H), mg, 0.090 mmol, (4,4,5,5-tetramethyl- 301.0/303.0 (M − H).sup.− 7.49 (dd, J 1.5, 0.7, 26.9%) 1,3,2-dioxaborolan-2- (ES.sup.−), at 3.87 min, 1H), 7.80 (s, 2H), yl)pyridine (92 mg, 97.1% (method B). 8.35 (dd, J 5.2, 0.7, 0.385 mmol) 1H). (xc) 6-(2-chloro-6- 6-bromo-5-(3- Mass (400 MHz, DMSO) δ: methylpyridin-4-yl)-5- fluorophenyl)-1,2,4- spectroscopy: m/z 2.40 (s, 3H), 7.13- (3-fluorophenyl)- triazin-3-amine (90 (Cl) 316.6/318.6 7.16 (m, 1H), 7.16- 1,2,4-triazin-3-amine mg, 0.334 mmol) and (M + H).sup.+ (ES.sup.+); 7.21 (m, 1H), 7.27- (54 mg, 0.171 mmol, 2-chloro-6-methyl-4- 314.8/316.8 (M − H).sup.− 7.29 (m, 1H), 7.29- 51.1%) (4,4,5,5-tetramethyl- (ES.sup.−), at 4.05 min, 7.39 (m, 2H), 7.40- 1,3,2-dioxaborolan-2- 99.9% (method B). 7.48 (m, 1H), 7.78 (s, yl)pyridine (98 mg, 2H). 0.385 mmol) (xci) 4-(3-amino-5-(4- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: fluorophenyl)-1,2,4- fluorophenyl)-1,2,4- spectroscopy: m/z 2.39 (s, 6H), 7.19- triazin-6-yl)-2,6- triazin-3-amine (90 320.7 (M + H).sup.+ 7.28 (m, 4H), 7.46 dimethylbenzonitrile mg, 0.334 mmol) and (ES.sup.+); 318.9 (M − H).sup.− (dd, J 8.8, 5.5, 2H), (66 mg, 0.206 mmol, 2,6-dimethyl-4- (ES.sup.−), at 4.40 min, 7.59 (s, 2H). 61.7%) (4,4,5,5-tetramethyl- 99.8% (method B). 1,3,2-dioxaborolan-2- yl)benzonitrile (99 mg, 0.385 mmol) (xcii) 6-(3-chloro-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: propoxyphenyl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 0.88 (t, J 7.4, 3H), phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) (Cl) 341.6/343.6 1.52-1.64 (m, 2H), 3-amine (71 mg, and 2-(3-chloro-5- (M + H).sup.+ (ES.sup.+); 3.80 (t, J 6.6, 2H), 0.202 mmol, 56.3%) propoxyphenyl)- 339.8/341.8 (M − H).sup.− 6.75-6.80 (m, 1H), 4,4,5,5-tetramethyl- (ES.sup.−), at 5.14 min, 6.94-6.99 (m, 2H), 1,3,2-dioxaborolane 96.9% (method B). 7.35-7.47 (m, 5H), (106 mg, 0.358 7.50 (s, 2H). mmol) (xciii) 6-(3-chloro-5- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe- fluorophenyl)-1,2,4- spectroscopy: m/z 7.25 (t, J 8.9, 2H), nyl)-5-(4- triazin-3-amine (90 (Cl) 369.4/371.5 7.47 (dd, J 8.8, 5.5, fluorophenyl)-1,2,4- mg, 0.334 mmol) and (M + H).sup.+ (ES.sup.+); 2H), 7.57 (s, 1H), triazin-3-amine (65 2-(3-chloro-5- 367.7/369.7 (M − H).sup.− 7.64 (s, 2H), 7.74 (s, mg, 0.169 mmol, (trifluoromethyl)phe- (ES.sup.−), at 5.03 min, 1H), 7.84 (s, 1H). 50.5%) nyl)-4,4,5,5- 95.8% (method B). tetramethyl-1,3,2- dioxaborolane (118 mg, 0.385 mmol) (xciv) 6-(2-chloropyridin-4- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: yl)-5-(4- fluorophenyl)-1,2,4- spectroscopy: m/z 7.21-7.33 (m, 3H), fluorophenyl)-1,2,4- triazin-3-amine (90 (Cl) 302.7/304.7 7.44-7.53 (m, 3H), triazin-3-amine (14 mg, 0.334 mmol) and (M + H).sup.+ (ES.sup.+); 7.75 (s, 2H), 8.35 (d, mg, 0.046 mmol, 2-chloro-4-(4,4,5,5- 300.9/302.9 (M − H).sup.− J 5.1, 1H). 13.76%) tetramethyl-1,3,2- (ES.sup.−), at 3.90 min, dioxaborolan-2- 99.2% (method B). yl)pyridine (92 mg, 0.385 mmol) (xcv) 6-(2-chloro-6- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: methylpyridin-4-yl)-5- fluorophenyl)-1,2,4- spectroscopy: m/z 2.40 (s, 3H), 7.15 (s, (4-fluorophenyl)- triazin-3-amine (90 (Cl) 316.7/318.7 1H), 7.23-7.31 (m, 1,2,4-triazin-3-amine mg, 0.334 mmol) and (M + H).sup.+ (ES.sup.+); 3H), 7.48 (dd, J 8.9, (37 mg, 0.117 mmol, 2-chloro-6-methyl-4- 314.9/316.9 (M − H).sup.− 5.5, 2H), 7.72 (s, 2H). 34.9%) (4,4,5,5-tetramethyl- (ES.sup.−), at 4.05 min, 1,3,2-dioxaborolan-2- 99.5% (method B). yl)pyridine (98 mg, 0.385 mmol) (xcvi) 4-(3-amino-5-(4- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: chlorophenyl)-1,2,4- chlorophenyl)-1,2,4- spectroscopy: m/z 2.40 (s, 6H), 7.25 (s, triazin-6-yl)-2,6- triazin-3-amine (90 (Cl) 336.6/338.6 2H), 7.40-7.50 (m, dimethylbenzonitrile mg, 0.315 mmol) and (M + H).sup.+ (ES.sup.+); 4H), 7.61 (s, 2H). (61 mg, 0.181 mmol, 2,6-dimethyl-4- 334.8/336.8 (M − H).sup.− 57.4%) (4,4,5,5-tetramethyl- (ES.sup.−), at 4.67 min, 1,3,2-dioxaborolan-2- 99.6% (method B). yl)benzonitrile (81 mg, 0.315 mmol) (xcvii) 6-(3-chloro-5- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe- chlorophenyl)-1,2,4- spectroscopy: m/z 7.40-7.51 (m, 4H), nyl)-5-(4- triazin-3-amine (90 (2 Cl) 385.3/387.4 7.59 (s, 1H), 7.67 (s, chlorophenyl)-1,2,4- mg, 0.315 mmol) and (M + H).sup.+ (ES.sup.+); 2H), 7.74 (s, 1H), triazin-3-amine (62.5 2-(3-chloro-5- 383.5/385.5 (M − H).sup.− 7.85 (s, 1H). mg, 0.157 mmol, (trifluoromethyl)phe- (ES.sup.−), at 5.25 min, 49.7%) nyl)-4,4,5,5- 96.6% (method B). tetramethyl-1,3,2- dioxaborolane (111 mg, 0.362 mmol) (xcviii) 5-(4-chlorophenyl)-6- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: (2-chloropyridin-4-yl)- chlorophenyl)-1,2,4- spectroscopy: m/z 7.27 (dd, J 5.2, 1.5, 1,2,4-triazin-3-amine triazin-3-amine (90 (2 Cl) 318.6/320.6 1H), 7.41-7.54 (m, (12.7 mg, 0.039 mg, 0.315 mmol) and (M + H).sup.+ (ES.sup.+); 5H), 7.77 (s, 2H), mmol, 12.44%) 2-chloro-4-(4,4,5,5- 316.8/318.8 (M − H).sup.− 8.35 (dd, J 5.2, 0.6, tetramethyl-1,3,2- (ES.sup.−), at 4.22 min, 1H). dioxaborolan-2- 98.2% (method B). yl)pyridine (87 mg, 0.362 mmol) (xcix) 6-(2-chloro-6- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: methylpyridin-4-yl)-5- chlorophenyl)-1,2,4- spectroscopy: m/z 2.41 (s, 3H), 7.14- (4-chlorophenyl)- triazin-3-amine (90 (2 Cl) 332.5/334.6 7.18 (m, 1H), 7.27- 1,2,4-triazin-3-amine mg, 0.315 mmol) (M + H).sup.+ (ES.sup.+); 7.31 (m, 1H), 7.42- (46.1 mg, 0.138 and 2-chloro-6- 330.8/332.7 (M − H).sup.− 7.54 (m, 4H), 7.74 (s, mmol, 43.9%) methyl-4-(4,4,5,5- (ES.sup.−), at 4.37 min, 2H). tetramethyl-1,3,2- 99.6% (method B). dioxaborolan-2- yl)pyridine (92 mg, 0.362 mmol) (c) 4-(3-amino-5-(3- 6-bromo-5-(3- Mass (400 MHz, DMSO) δ: chlorophenyl)-1,2,4- chlorophenyl)-1,2,4- spectroscopy: m/z 2.40 (s, 6H), 7.20 triazin-6-yl)-2,6- triazin-3-amine (90 (Cl) 336.6/338.6 (ddd, J 7.8, 1.6, 1.0, dimethylbenzonitrile mg, 0.315 mmol) and (M + H).sup.+ (ES.sup.+); 1H), 7.36 (app t, J (64.3 mg, 0.190 2,6-dimethyl-4- 334.8/336.8 (M − H).sup.− 7.9, 1H), 7.26 (s, 2H), mmol, 60.3%) (4,4,5,5-tetramethyl- (ES.sup.−), at 4.59 min, 7.53 (ddd, J 8.0, 2.2, 1,3,2-dioxaborolan-2- 99.3% (method B). 1.0, 1H), 7.59 (app t, yl)benzonitrile (81 J 1.7, 1H), 7.64 (s, mg, 0.315 mmol) 2H). (ci) 6-(3-chloro-5- 6-bromo-5-(3- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe- chlorophenyl)-1,2,4- spectroscopy: m/z 7.24-7.29 (m, 1H), nyl)-5-(3- triazin-3-amine (90 (2 Cl) 385.3/387.4 7.39 (app td, J 7.8, chlorophenyl)-1,2,4- mg, 0.315 mmol) and (M + H).sup.+ (ES.sup.+); 0.6, 1H), 7.51-7.57 triazin-3-amine (67.6 2-(3-chloro-5- 383.5/385.6 (M − H).sup.− (m, 2H), 7.57-7.61 mg, 0.169 mmol. (trifluoromethyl)phe- (ES.sup.−), at 5.20 min, (m, 1H), 7.69 (s, 2H), 53.7%) nyl)-4,4,5,5- 96.4% (method B). 7.75-7.79 (m, 1H), tetramethyl-1,3,2- 7.84-7.88 (m, 1H). dioxaborolane (111 mg, 0.362 mmol) (cii) 5-(3-chlorophenyl)-6- 6-bromo-5-(3- Mass (400 MHz, DMSO) δ: (2-chloropyridin-4-yl)- chlorophenyl)-1,2,4- spectroscopy: m/z 7.25-7.29 (m, 1H), 1,2,4-triazin-3-amine triazin-3-amine (90 (2 Cl) 318.6/320.6 7.31 (dd, J 5.2, 1.5, (32.4 mg, 0.101 mg, 0.315 mmol) (M + H).sup.+ (ES.sup.+); 1H), 7.40 (app t, J mmol, 32.0%) and 2-chloro-4- 316.8/318.8 (M − H).sup.− 11.9, 1H), 7.49-7.53 (4,4,5,5-tetramethyl- (ES.sup.−), at 4.17 min, (m, 1H), 7.54-7.61 1,3,2-dioxaborolan-2- 99.0% (method B). (m, 2H), 7.80 (s, 2H), yl)pyridine (87 mg, 8.36 (dd, J 5.2, 0.6, 0.362 mmol) 1H). (ciii) 6-(2-chloro-6- 6-bromo-5-(3- Mass (400 MHz, DMSO) δ: methylpyridin-4-yl)-5- chlorophenyl)-1,2,4- spectroscopy: m/z 2.41 (s, 3H), 7.19- (3-chlorophenyl)- triazin-3-amine (90 (2 Cl) 332.5/334.6 7.15 (m, 1H), 7.26 1,2,4-triazin-3-amine mg, 0.315 mmol) and (M + H).sup.+ (ES.sup.+); (ddd, J 7.8, 1.6, 1.1, (51.3 mg, 0.154 2-chloro-6-methyl-4- 330.8/332.7 (M − H).sup.− 1H), 7.33-7.29 (m, mmol, 49.0%) (4,4,5,5-tetramethyl- (ES.sup.−), at 4.30 min, 1H), 7.41 (app t, J 1,3,2-dioxaborolan-2- 100% (method B). 7.9, 1H), 7.57 (ddd, J yl)pyridine (92 mg, 8.0, 2.2, 1.0, 1H), 0.362 mmol) 7.60 (app t, J 1.7, 1H), 7.78 (s, 2H). (civ) 4-(3-amino-6-(3- 4-(3-amino-6-bromo- Mass (400 MHz, DMSO) δ: chloro-5- 1,2,4-triazin-5- spectroscopy: m/z 7.54-7.58 (m, 1H), (trifluoromethyl)phe- yl)benzonitrile (90 (Cl) 376.4/378.4 7.57-7.62 (m, 2H), nyl)-1,2,4-triazin-5- mg, 0.326 mmol) and (M + H).sup.+ (ES.sup.+); 7.65-7.81 (m, 3H), yl)benzonitrile (64.7 2-(3-chloro-5- 374.6/376.6 (M − H).sup.− 7.83-7.87 (m, 1H), mg, 0.171 mmol, (trifluoromethyl)phe- (ES.sup.−), at 4.67 min, 7.87-7.93 (m, 2H). 52.5%) nyl)-4,4,5,5- 99.4% (method B). tetramethyl-1,3,2- dioxaborolane (115 mg, 0.375 mmol) (cv) 4-(3-amino-6-(2- 4-(3-amino-6-bromo- Mass (400 MHz, DMSO) δ: chloro-6- 1,2,4-triazin-5- spectroscopy: m/z 2.40 (s, 3H), 7.16 (s, methylpyridin-4-yl)- yl)benzonitrile (90 (Cl) 323.6/325.6 1H), 7.26 (s, 1H), 1,2,4-triazin-5- mg, 0.326 mmol) (M + H).sup.+ (ES.sup.+); 7.58-7.64 (m, 2H), yl)benzonitrile (30.5 and 2-chloro-6- 321.8/323.8 (M − H).sup.− 7.82 (s, 2H), 7.88- mg, 0.093 mmol, methyl-4-(4,4,5,5- (ES.sup.−), at 3.65 min, 7.94 (m, 2H). 28.6%) tetramethyl-1,3,2- 98.6% (method B). dioxaborolan-2- yl)pyridine (95 mg, 0.375 mmol) (cvi) 4-(3-amino-5-(3- 6-bromo-5-(3-chloro- Mass (400 MHz, DMSO) δ: chloro-5- 5-fluorophenyl)- spectroscopy: m/z 2.41 (s, 6H), 7.11- fluorophenyl)-1,2,4- 1,2,4-triazin-3-amine 354, 356 (M + H).sup.+ 7.19 (m, 1H), 7.27 (s, triazin-6-yl)-2,6- (90 mg, 0.297 mmol) (ES.sup.+); 352, 354 (M − 2H), 7.34-7.38 (m, dimethylbenzonitrile and 2,6-dimethyl-4- H).sup.− (ES.sup.−), at 1H), 7.55-7.62 (m, (57 mg, 52%) (4,4,5,5-tetramethyl- 4.72 min, 95% 1H), 7.70 (s, 2H). 1,3,2-dioxaborolan-2- (method B). yl)benzonitrile (88 mg, 0.341 mmol) (cvii) 5-(3-chloro-5- 6-bromo-5-(3-chloro- Mass (400 MHz, DMSO) δ: fluorophenyl)-6-(2- 5-fluorophenyl)- spectroscopy: m/z 2.42 (s, 3H), 7.19 (s, chloro-6- 1,2,4-triazin-3-amine 350, 352 (M + H).sup.+ 1H), 7.20-7.26 (m, methylpyridin-4-yl)- (90 mg, 0.297 mmol) (ES.sup.+); 348, 350 (M − 1H), 7.30 (s, 1H), 1,2,4-triazin-3-amine and 2-chloro-6- H).sup.− (ES.sup.−), at 4.2 min, 7.38 (s, 1H), 7.58- (18 mg, 16%) methylpyridin-4- 95% (method B). 7.66 (m, 1H), 7.84 (s, ylboronic acid (58.4 2H). mg, 0.341 mmol) (cviii) 6-(3-chloro-5- 6-bromo-5-(3-chloro- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe- 5-fluorophenyl)- spectroscopy: m/z 7.22 (ddd, J 9.3, 2.4, nyl)-5-(3-chloro-5- 1,2,4-triazin-3-amine 403, 405 (M + H).sup.+ 1.4, 1H), 7.34-7.39 fluorophenyl)-1,2,4- (90 mg, 0.297 mmol) (ES.sup.+); 401, 403 (M − (m, 1H), 7.58-7.64 triazin-3-amine (28 and 2-(3-chloro-5- H).sup.− (ES.sup.−), at (m, 2H), 7.76 (s, 2H), mg, 22%) (trifluoromethyl)phe- 5.28 min, 93% 7.79 (s, 1H), 7.89 (s, nyl)-4,4,5,5- (method B). 1H). tetramethyl-1,3,2- dioxaborolane (105 mg, 0.341 mmol) (cix) 6-(3-chloro-5- 6-bromo-5-(3,5- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe- difluorophenyl)-1,2,4- spectroscopy: m/z 7.08-7.20 (m, 2H), nyl)-5-(3,5- triazin-3-amine (90 387, 389 (M + H).sup.+ 7.42 (tt, J 9.3, 2.4, difluorophenyl)-1,2,4- mg, 0.314 mmol) and (ES.sup.+); 385, 387 (M − 1H), 7.58 (s, 1H), triazin-3-amine (54 2-(3-chloro-5- H).sup.− (ES.sup.−), at 7.66-7.86 (m, 3H), mg, 43%) (trifluoromethyl)phe- 5.09 min, 96% 7.89 (s, 1H). nyl)-4,4,5,5- (method B). tetramethyl-1,3,2- dioxaborolane (96 mg, 0.314 mmol) (cx) 6-(2-chloro-6- 6-bromo-5-(3,5- Mass (400 MHz, DMSO) δ: methylpyridin-4-yl)-5- difluorophenyl)-1,2,4- spectroscopy: m/z 2.42 (s, 3H), 7.11- (3,5-difluorophenyl)- triazin-3-amine (90 334, 336 (M + H).sup.+ 7.18 (m, 2H), 7.17- 1,2,4-triazin-3-amine mg, 0.314 mmol) and (ES.sup.+); 332, 334 (M − 7.20 (m, 1H), 7.25- (29 mg, 27%) 2-chloro-6- H).sup.− (ES.sup.−), at 7.31 (m, 1H), 7.44 (tt, methylpyridin-4- 4.17 min, 98% J 9.3, 2.4, 1H), 7.82 ylboronic acid (61.8 (method B). (s, 2H). mg, 0.361 mmol) (cxi) 4-(3-amino-5-(3,5- 6-bromo-5-(3,5- Mass (400 MHz, DMSO) δ: difluorophenyl)-1,2,4- difluorophenyl)-1,2,4- spectroscopy: m/z 2.41 (s, 6H), 7.05- triazin-6-yl)-2,6- triazin-3-amine (90 338 (M + H).sup.+ (ES.sup.+); 7.14 (m, 2H), 7.26 (s, dimethylbenzonitrile mg, 0.314 mmol) and 336 (M − H).sup.− (ES.sup.−), at 2H), 7.40 (tt, J 9.3, (48 mg, 45%) 2,6-dimethyl-4- 4.45 min, 100% 2.4, 1H), 7.69 (s, 2H). (4,4,5,5-tetramethyl- (method B). 1,3,2-dioxaborolan-2- yl)benzonitrile (93 mg, 0.361 mmol) (cxii) 4-(3-amino-5-(3- 6-bromo-5-(3-chloro- Mass (400 MHz, DMSO) δ: chloro-4- 4-fluorophenyl)- spectroscopy: m/z 2.41 (s, 6H), 7.22- fluorophenyl)-1,2,4- 1,2,4-triazin-3-amine 354, 356 (M + H).sup.+ 7.28 (m, 1H), 7.28 (s, triazin-6-yl)-2,6- (90 mg, 0.297 mmol) (ES.sup.+); 352, 354 (M − 2H), 7.37-7.44 (m, dimethylbenzonitrile and 2,6-dimethyl-4- H).sup.− (ES.sup.−), at 1H), 7.66 (s, 2H), (35 mg, 33%) (4,4,5,5-tetramethyl- 4.67 min, 98% 7.75 (dd, J 7.2, 2.2, 1,3,2-dioxaborolan-2- (method B). 1H). yl)benzonitrile (88 mg, 0.341 mmol) (cxiii) 5-(3-chloro-4- 6-bromo-5-(3-chloro- Mass (400 MHz, DMSO) δ: fluorophenyl)-6-(2- 4-fluorophenyl)- spectroscopy: m/z 2.42 (s, 3H), 7.21 (s, chloro-6- 1,2,4-triazin-3-amine 350, 352 (M + H).sup.+ 1H), 7.30 (s, 1H), methylpyridin-4-yl)- (90 mg, 0.297 mmol) (ES.sup.+); 348, 350 (M − 7.30-7.35 (m, 1H), 1,2,4-triazin-3-amine and 2-chloro-6- H).sup.− (ES.sup.−), at 7.46 (app t, J 8.9, (40 mg, 38%) methylpyridin-4- 4.39 min, 99% 1H), 7.66-7.91 (m, ylboronic acid (61.8 (method B). 3H). mg, 0.361 mmol) (cxiv) 5-(3-chloro-4- 6-bromo-5-(3,5- Mass (400 MHz, DMSO) δ: fluorophenyl)-6-(2- difluorophenyl)-1,2,4- spectroscopy: m/z 7.30 (dd, J 5.2, 1.5, chloropyridin-4-yl)- triazin-3-amine (90 336, 338 (M + H).sup.+ 1H), 7.34 (ddd, J 8.6, 1,2,4-triazin-3-amine mg, 0.314 mmol) and (ES.sup.+); 334, 336 (M − 4.7, 2.2, 1H), 7.42- (9 mg, 9%) 2-chloropyridin-4- H).sup.− (ES.sup.−), at 4.2 min, 7.51 (m, 1H), 7.53- ylboronic acid (61.8 98% (method B). 7.57 (m, 1H), 7.75 mg, 0.361 mmol) (dd, J 7.2, 2.1, 1H), 7.82 (s, 2H), 8.37 (dd, J 5.2, 0.6, 1H). (cxv) 5-(3-chloro-4- 6-bromo-5-(3-chloro- Mass (400 MHz, DMSO) δ: fluorophenyl)-6-(3- 4-fluorophenyl)- spectroscopy: m/z 7.33 (ddd, J 8.6, 4.7, chloro-5- 1,2,4-triazin-3-amine 403, 405 (M + H).sup.+ 2.2, 1H), 7.45 (app t, (trifluoromethyl)phe- (90 mg, 0.297 mmol) (ES.sup.+); 401, 403 (M − J 8.9, 1H), 7.61 (s, nyl)-1,2,4-triazin-3- and 2-(3-chloro-5- H).sup.− (ES.sup.−), at 1H), 7.63-7.76 (m, amine (50 mg, 42%) (trifluoromethyl)phe- 5.22 min, 100% 3H), 7.78 (s, 1H), nyl)-4,4,5,5- (method B). 7.88 (s, 1H). tetramethyl-1,3,2- dioxaborolane (91 mg, 0.297 mmol) (cxvi) 4-(3-amino-5-(3,4- 6-bromo-5-(3,4- Mass (400 MHz, DMSO) δ: difluorophenyl)-1,2,4- difluorophenyl)-1,2,4- spectroscopy: m/z 2.41 (s, 6H), 7.10- triazin-6-yl)-2,6- triazin-3-amine (90 338 (M + H).sup.+ (ES.sup.+); 7.20 (m, 1H), 7.26 (s, dimethylbenzonitrile mg, 0.314 mmol) and 336 (M − H).sup.− (ES.sup.−), at 2H), 7.40-7.50 (m, (35 mg, 33%) 2,6-dimethyl-4- 4.49 min, 99% 1H), 7.54 (ddd, J (4,4,5,5-tetramethyl- (method B). 11.4, 7.8, 2.1, 1H), 1,3,2-dioxaborolan-2- 7.65 (s, 2H). yl)benzonitrile (93 mg, 0.361 mmol) (cxvii) 6-(2-chloro-6- 6-bromo-5-(3,4- Mass (400 MHz, DMSO) δ: methylpyridin-4-yl)-5- difluorophenyl)-1,2,4- spectroscopy: m/z 2.41 (s, 3H), 7.20 (s, (3,4-difluorophenyl)- triazin-3-amine (90 334, 336 (M + H).sup.+ 1H), 7.20-7.24 (m, 1,2,4-triazin-3-amine mg, 0.314 mmol) and (ES.sup.+); 332, 334 (M − 1H), 7.28 (s, 1H), (28 mg, 27%) 2-chloro-6- H).sup.− (ES.sup.−), at 7.44-7.62 (m, 2H), methylpyridin-4- 4.15 min, 99% 7.79 (s, 2H). ylboronic acid (61.8 (method B). mg, 0.361 mmol) (cxviii) 6-(2-chloropyridin-4- 6-bromo-5-(3,4- Mass (400 MHz, DMSO) δ: yl)-5-(3,4- difluorophenyl)-1,2,4- spectroscopy: m/z 7.18-7.26 (m, 1H), difluorophenyl)-1,2,4- triazin-3-amine (90 320, 322 (M + H).sup.+ 7.28 (dd, J 5.2, 1.5, triazin-3-amine (10 mg, 0.314 mmol) and (ES.sup.+); 318, 320 (M − 1H), 7.44-7.62 (m, mg, 10%) 2-chloropyridin-4- H).sup.− (ES.sup.−), at 4.0 min, 3H), 7.81 (s, 2H), ylboronic acid (56.7 96% (method B). 8.36 (dd, J 5.2, 0.6, mg, 0.361 mmol) 1H). (cxix) 6-(3-chloro-5- 6-bromo-5-(3,4- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe- difluorophenyl)-1,2,4- spectroscopy: m/z 7.17-7.26 (m, 1H), nyl)-5-(3,4- triazin-3-amine (90 387, 389 (M + H).sup.+ 7.43-7.57 (m, 2H), difluorophenyl)-1,2,4- mg, 0.314 mmol) and (ES.sup.+); 385, 387 (M − 7.59 (s, 1H), 7.71 (s, triazin-3-amine (16 2-(3-chloro-5- H).sup.− (ES.sup.−), at 2H), 7.76 (s, 1H), mg, 13%) (trifluoromethyl)phe- 5.07 min, 95% 7.87 (s, 1H). nyl)-4,4,5,5- (method B). tetramethyl-1,3,2- dioxaborolane (96 mg, 0.314 mmol) (cxx) 6-(3-chloro-5- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe- (methoxymethyl)phe- spectroseopy: m/z 3.26 (s, 3H), 4.43 (s, nyl)-5-(4- nyl)-1,2,4-triazin-3- (Cl) 395.3/397.3 2H), 7.33 (d, J 8.5, (methoxymethyl)phe- amine (90 mg, 0.305 (M + H).sup.+ (ES.sup.+); 2H), 7.39 (d, J 8.4, nyl)-1,2,4-triazin-3- mmol) and 2-(3- 393.5/395.5 (M − H).sup.− 2H), 7.57 (s, 1H), amine (36 mg, 0.087 chloro-5- (ES.sup.−), at 4.93 min, 7.64 (s, 2H), 7.72 (s, mmol, 28.7%) (trifluoromethyl)phe- 95.9% (method B). 1H), 7.83 (s, 1H). nyl)-4,4,5,5- tetramethyl-1,3,2- dioxaborolane (107 mg, 0.351 mmol) (cxxi) 6-(2-chloro-6- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: methylpyridin-4-yl)-5- (methoxymethyl)phe- spectroscopy: m/z 2.39 (s, 3H), 3.28 (s, (4- nyl)-1,2,4-triazin-3- (Cl) 342.6/344.5 3H), 4.45 (s, 2H), (methoxymethyl)phe- amine (90 mg, 0.305 (M + H).sup.+ (ES.sup.+); 7.08-7.14 (m, 1H), nyl)-1,2,4-triazin-3- mmol) and 2-chloro- 340.8/342.8 (M − H).sup.− 7.25-7.31 (m, 1H), amine (23 mg, 0.066 6-methyl-4-(4,4,5,5- (ES.sup.−), at 3.93 min, 7.35 (d, J 8.5, 2H), mmol, 21.49%) tetramethyl-1,3,2- 97.4% (method B). 7.41 (d, J 8.4, 2H), dioxaborolan-2- 7.72 (s, 2H). yl)pyridine (89 mg, 0.351 mmol) (cxxii) 6-(2,6- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: dimethylpyridin-4-yl)- fluorophenyl)-1,2,4- spectroscopy: m/z 2.40 (s, 6H), 7.10 (s, 5-(4-fluorophenyl)- triazin-3-amine (90 296.8 (M + H).sup.+ 2H), 7.20-7.31 (m, 1,2,4-triazin-3-amine mg, 0.334 mmol) and (ES.sup.+); 295.0 (M − H).sup.− 2H), 7.40-7.53 (m, (23 mg, 0.078 mmol, 2,6-dimethylpyridin- (ES.sup.−), at 3.85 min, 2H), 7.68 (s, 2H). 23.19%) 4-ylboronic acid 99.6% (method B). (58.1 mg, 0.385 mmol) (cxxiii) 6-(3-chloro-5- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: methylphenyl)-5-(4- fluorophenyl)-1,2,4- spectroscopy: m/z 2.25 (s, 3H), 7.10- fluorophenyl)-1,2,4- triazin-3-amine (90 (Cl) 315.6/317.6 7.17 (m, 2H), 7.19- triazin-3-amine (67 mg, 0.334 mmol) and (M + H).sup.+ (ES.sup.+); 7.28 (m, 3H), 7.42- mg, 0.212 mmol, 3-chloro-5- 313.8/315.8 (M − H).sup.− 7.49 (m, 2H), 7.51 (s, 63.3%) methylphenylboronic (ES.sup.−), at 4.82 min, 2H). acid (65.5 mg, 0.385 99.4% (method B). mmol) (cxxiv) 6-(6-fluoropyridin-3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: yl)-5-phenyl-1,2,4- 1,2,4-triazin-3-amine spectroscopy: 7.17 (ddd, J 8.5, 2.8, triazin-3-amine (47 (75 mg, 0.299 mmol) m/z 268.2 (M + H).sup.+ 0.5, 1H), 7.53 (s, 2H), mg, 0.173 mmol, and 2-fluoro-5- (ES.sup.+); 266.3 (M − H).sup.− 7.35-7.48 (m, 5H), 58.0%) (4,4,5,5-tetramethyl- (ES.sup.−), at 3.54 min, 7.86-7.94 (m, 1H), 1,3,2-dioxaborolan-2- 98.5% (method B). 8.13-8.19 (m, 1H). yl)pyridine (77 mg, 0.344 mmol) (cxxv) 6-(3,5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: dimethylisoxazol-4- 1,2,4-triazin-3-amine spectroscopy: 1.85 (s, 3H), 2.02 (s, yl)-5-phenyl-1,2,4- (75 mg, 0.299 mmol) m/z 268.2 (M + H).sup.+ 3H), 7.38-7.55 (m, triazin-3-amine (8 and 5- (ES.sup.+); 266.4 (M − H).sup.− 7H). mg, 0.030 mmol, dimethylisoxazol-4- (ES.sup.−), at 3.48 min, 10.02%) ylboronic acid (42.1 96.2% (method B). mg, 0.299 mmol) (cxxvi) 6-(3,5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: diisopropylphenyl)-5- 1,2,4-triazin-3-amine spectroscopy: 1.06 (d, J 6.9, 12H), phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) m/z 333.3 (M + H).sup.+ 2.78 (hept, J 6.8, 2H), 3-amine (84.5 mg, and 2-(3,5- (ES.sup.+); 331.5 (M − H).sup.− 6.96-7.06 (m, 3H), 0.254 mmol, 70.9%) diisopropylphenyl)- (ES.sup.−), at 5.24 min, 7.31-7.45 (m, 7H). 4,4,5,5-tetramethyl- 100% (254 nm). 1,3,2-dioxaborolane (119 mg, 0.412 mmol) (cxxvii) 6-(3-fluoro-5-(2,2,2- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: trifluoroethoxy)phenyl)- 1,2,4-triazin-3-amine spectroscopy: 4.73 (q, J 8.8, 2H), 5-phenyl-1,2,4- (90 mg, 0.358 mmol) m/z 365.2 (M + H).sup.+ 6.76 (ddd, J 9.5, 2.3, triazin-3-amine (80 and 3-fluoro-5-(2,2,2- (ES.sup.+); 363.4 (M − H).sup.− 1.4, 1H), 6.89-6.94 mg, 0.214 mmol, trifluoroethoxy)phenyl- (ES.sup.−), at 4.43 min, (m, 1H), 6.99 (dt, J 59.7%) boronic acid (98 mg, 97.4% (method B). 10.7, 2.3, 1H), 7.52 0.412 mmol) (s, 2H), 7.34-7.48 (m, 5H). (cxxviii) N-(4-(3-amino-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: phenyl-1,2,4-triazin- 1,2,4-triazin-3-amine spectroscopy: 2.04 (s, 3H), 7.34- 6-yl)-2- (90 mg, 0.358 mmol) m/z 374.1 (M + H).sup.+ 7.48 (m, 5H), 7.49- (trifluoromethyl)phe- and N-(4-(4,4,5,5- (ES.sup.+); 372.3 (M − H).sup.− 7.68 (m, 5H), 9.55 (s, nyl)acetamide (99 mg, tetramethyl-1,3,2- (ES.sup.−), at 3.52 min, 1H). 0.255 mmol, 71.0%) dioxaborolan-2-yl)-2- 98.9% (method B). (trifluoromethyl)phe- nyl)acetamide (136 mg, 0.412 mmol) (cxxix) 5-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)-2- 1,2,4-triazin-3-amine spectroscopy: 7.34-7.42 (m, 4H), fluorobenzonitrile (43 (90 mg, 0.358 mmol) m/z 292.1 (M + H).sup.+ 7.42-7.47 (m, 1H), mg, 0.147 mmol, and 3-cyano-4- (ES.sup.+); 290.3 (M − H).sup.− 7.50 (t, J 9.2, 1H), 40.9%) fluorophenylboronic (ES.sup.−), at 3.79 min, 7.57 (s, 2H), 7.67 acid (68.0 mg, 0.412 99.3% (method B). (ddd, J 8.8, 5.3, 2.3, mmol) 1H), 7.89 (dd, J 6.2, 2.3, 1H). (cxxx) 3-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)- 1,2,4-triazin-3-amine spectroscopy: 2.60 (s, 3H), 2.89 (s, N,N- (90 mg, 0.358 mmol) m/z 320.2 (M + H).sup.+ 3H), 7.19-7.24 (m, dimethylbenzamide and 3- (ES.sup.+); 318.4 (M − H).sup.− 1H), 7.31-7.38 (m, (80 mg, 0.251 mmol, (dimethylcarbamoyl) (ES.sup.−), at 3.30 min, 3H), 7.38-7.47 (m, 69.9%) phenylboronic acid 100% (method B). 6H), 7.48-7.52 (m, (80 mg, 0.412 mmol) 1H). (cxxxi) 6-(1-methyl-1H- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: pyrazol-4-yl)-5- 1,2,4-triazin-3-amine spectroscopy: 3.77 (s, 3H), 7.04 (d, phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) m/z 253.2 (M+H).sup.+ J 0.7, 1H), 7.24 (s, 3-amine (43 mg, and 1-methyl-4- (ES.sup.+); 251.4 (M − H).sup.− 2H), 7.43-7.56 (m, 0.168 mmol, 47.0%) (4,4,5,5-tetramethyl- (ES.sup.−), at 3.15 min, 5H), 7.64 (s, 1H). 1,3,2-dioxaborolan-2- 98.8% (method B). yl)-1H-pyrazole (86 mg, 0.412 mmol) (cxxxii) 4-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)-1- 1,2,4-triazin-3-amine spectroscopy: 3.39 (s, 3H), 6.14 methylpyridin-2(1H)- (90 mg, 0.358 mmol) m/z 280.1 (M + H).sup.+ (dd, J 7.0, 2.0, 1H), one (33 mg, 0.115 and 1-methyl-4- (ES.sup.+); 278.4 (M − H).sup.− 6.32 (d, J 1.7, 1H), mmol, 32.1%) (4,4,5,5-tetramethyl- (ES.sup.−), at 2.92 min, 7.38-7.54 (m, 5H), 1,3,2-dioxaborolan-2- 97.4% (method B). 7.56-7.70 (m, 3H). yl)pyridin-2(1H)-one (97 mg, 0.412 mmol) (cxxxiii) 6-(3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: morpholinophenyl)-5- 1,2,4-triazin-3-amine spectroscopy: 2.87-3.02 (m, 4H), phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) m/z 334.3 (M + H).sup.+ 3.58-3.72 (m, 4H), 3-amine (65 mg, and 4-(3-(4,4,5,5- (ES.sup.+); 332.4 (M − H).sup.− 6.74 (d, J 7.7, 1H), 0.192 mmol, 53.6%) tetramethyl-1,3,2- (ES.sup.−), at 4.07 min, 6.86-6.94 (m, 2H), dioxaborolan-2- 98.6% (method B). 7.16 (t, J 7.6, 1H), yl)phenyl)morpholine 7.28-7.45 (m, 7H). (119 mg, 0.412 mmol) (cxxxiv) 6-(1-benzyl-1H- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: pyrazol-4-yl)-5- 1,2,4-triazin-3-amine spectroscopy: 5.26 (s, 2H), 7.12- phenyl-1,2,4-triazin- (90 mg, 0.358 mmol) m/z 329.3 (M + H).sup.+ 7.18 (m, 2H), 7.20 (d, 3-amine (78 mg, and 1-benzyl-4- (ES.sup.+); 327.5 (M − H).sup.− J 0.7, 1H), 7.26 (s, 0.237 mmol, 66.1%) (4,4,5,5-tetramethyl- (ES.sup.−), at 4.07 min, 2H), 7.27-7.37 (m, 1,3,2-dioxaborolan-2- 99.8% (method B). 3H), 7.40-7.53 (m, yl)-1H-pyrazole (117 5H), 7.67 (d, J 0.7, mg, 0.412 mmol) 1H). (cxxxv) 6-(2- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: methoxypyrimidin-5- 1,2,4-triazin-3-amine spectroscopy: 3.91 (s, 3H), 7.38- yl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) m/z 281.2 (M + H).sup.+ 7.49 (m, 5H), 7.55 (s, triazin-3-amine (34 and 2- (ES.sup.+); 279.4 (M − H).sup.− 2H), 8.50 (s, 2H). mg, 0.119 mmol, methoxypyrimidin-5- (ES.sup.−), at 3.42 min, 33.2%) ylboronic acid (63.5 98.2% (method B). mg, 0.412 mmol) (cxxxvi) 6-(6-methoxypyridin- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 3-yl)-5-phenyl-1,2,4- 1,2,4-triazin-3-amine spectroscopy: 3.84 (s, 3H), 6.78 triazin-3-amine (50 (90 mg, 0.358 mmol) m/z 280.1 (M + H).sup.+ (dd, J 8.6, 0.7, 1H), mg, 0.176 mmol, and 6- (ES.sup.+); 278.4 (M − H).sup.− 7.34-7.48 (m, 7H), 49.1%) methoxypyridin-3- (ES.sup.−), at 3.88 min, 7.60 (dd, J 8.6, 2.5, ylboronic acid (63.0 98.3% (method B). 1H), 8.10 (dd, J 2.5, mg, 0.412 mmol) 0.7, 1H). (cxxxvii) 6-(3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (methylsulfinyl)phe- 1,2,4-triazin-3-amine spectroscopy: 2.58 (s, 3H), 7.32- nyl)-5-phenyl-1,2,4- (90 mg, 0.358 mmol) m/z 311.1 (M + H).sup.+ 7.47 (m, 5H), 7.47- triazin-3-amine (70 and with 3- (ES.sup.+); 309.3 (M − H).sup.− 7.57 (m, 4H), 7.58- mg, 0.217 mmol, (methylsulfinyl)phenyl- (ES.sup.−), at 3.29 min, 7.60 (m, J 1.3, 1H), 60.4%) boronic acid (76 mg, 96.0% (method B). 7.63 (dt, J 7.3, 1.7, 0.412 mmol) 1H). (cxxxviii) 4-(3-amino-6-(2- 4-(3-amino-6-bromo- Mass (400 MHz, DMSO) δ: chloropyridin-4-yl)- 1,2,4-triazin-5- spectroscopy: 7.25 (dd, J 5.2, 1.5, 1,2,4-triazin-5- yl)benzonitrile (90 m/z (Cl) 1H), 7.51 (dd, J 1.5, yl)benzonitrile (11.3 mg, 0.326 mmol) and 309.6/311.7 (M + H).sup.+ 0.7, 1H), 7.58-7.65 mg, 0.036 mmol, 2-chloro-4-(4,4,5,5- (ES.sup.+); 307.9/309.9 (m, 2H), 7.85 (s, 2H), 10.93%) tetramethyl-1,3,2- (M − H).sup.− (ES.sup.−), at 7.89-7.94 (m, 2H), dioxaborolan-2- 3.50 min, 97.3% 8.34 (dd, J 5.2, 0.6, yl)pyridine (90 mg, (method B). 1H). 0.375 mmol) (cxxxix) 4-(3-amino-5-(4- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: (methoxymethyl)phe- (methoxymethyl)phe- spectroscopy: 2.38 (s, 6H), 4.43 (s, nyl)-1,2,4-triazin-6- nyl)-1,2,4-triazin-3- m/z 346.6 (M + H).sup.+ 2H), 7.23 (s, 2H), yl)-2,6- amine (90 mg, 0.305 (ES.sup.+); 344.8 (M − H).sup.− 7.32 (d, J 8.5, 2H), dimethylbenzonitrile mmol) and 2,6- (ES.sup.−), at 4.25 min, 7.39 (d, J 8.4, 2H), (47 mg, 0.132 mmol, dimethyl-4-(4,4,5,5- 96.7% (method B). 7.67 (s, 2H). 43.2%) tetramethyl-1,3,2- dioxaborolan-2- yl)benzonitrile (78 mg, 0.305 mmol) (cxl) 6-(2-chloropyridin-4- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: yl)-5-(4- (methoxymethyl)phe- spectroscopy: 3.29 (s, 3H), 4.45 (s, (methoxymethyl)phe- nyl)-1,2,4-triazin-3- m/z (Cl) 2H), 7.28 (dd, J 5.2, nyl)-1,2,4-triazin-3- amine (90 mg, 0.305 328.6/330.5 (M + H).sup.+ 1.5, 1H), 7.35 (d, J amine (26 mg, 0.077 mmol) and 2-chloro- (ES.sup.+); 326.8/328.8 8.5, 2H), 7.42 (d, J mmol, 25.3%) 4-(4,4,5,5- (M − H).sup.− (ES.sup.−), at 8.4, 2H), 7.48 (dd, J tetramethyl-1,3,2- 3.79 min, 97.4% 1.5, 0.7, 1H), 7.74 (s, dioxaborolan-2- (method B). 2H), 8.33 (dd, J 5.2, yl)pyridine (84 mg, 0.7, 1H). 0.351 mmol) (cxli) 6(E)-5-phenyl-6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: styryl-1,2,4-triazin-3- 1,2,4-triazin-3-amine spectroscopy: 7.09 (d, J 16.0, 1H), amine (27 mg, 0.098 (90 mg, 0.358 mmol) m/z z 275.1 (M + H).sup.+ 7.28 (t, J 7.3, 1H), mmol, 27.5%) and (E)-styrylboronic (ES.sup.+), at 4.78 min, 7.36 (t, J 7.5, 2H), acid (61.0 mg, 0.412 93.2% (method B). 7.44 (s, 2H), 7.49 (d, mmol) J 7.3, 2H), 7.55- 7.62 (m, 4H), 7.64- 7.70 (m, 2H). (cxlii) 6-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6- 1,2,4-triazin-3-amine spectroscopy: 3.48 (s, 2H), 6.80 yl)indolin-2-one (34 (90 mg, 0.358 mmol) m/z 304.7 (M + H).sup.+ (dd, J 7.6, 1.6, 1H), mg, 0.111 mmol, and 2-oxoindolin-6- (ES.sup.+); 302.9 (M − H).sup.− 6.86-6.90 (m, 1H), 31.0%) ylboronic acid (72.9 (ES.sup.−), at 3.47 min, 7.11 (d, J 7.7, 1H), mg, 0.412 mmol) 99.1% (method B). 7.31-7.47 (m, 7H), 10.38 (s, 1H). (cxliii) tert-butyl 5-(3-amino- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 5-phenyl-1,2,4- 1,2,4-triazin-3-amine spectroscopy: 1.45 (s, 9H), 3.28 (s, triazin-6-yl)pyridin-2- (90 mg, 0.358 mmol) m/z 379.5 (M + H).sup.+ 3H), 7.35-7.48 (m, yl(methyl)carbamate and 6-(tert- (ES.sup.+); 377.8 (M − H).sup.− 5H), 7.49 (s, 2H), (120 mg, 0.308 butoxycarbonyl(meth- (ES.sup.−), at 4.53 min, 7.60 (dd, J 8.7, 0.8, mmol, 42.9%) yl)amino)pyridin-3- 97.1% (method B). 1H), 7.66 (dd, J 8.7, ylboronic acid (181 2.4, 1H), 8.30 (dd, J mg, 0.717 mmol) 2.4, 0.8, 1H). (cxliv) 5-(3-chloro-5- 6-bromo-5-(3-chloro- Mass (400 MHz, DMSO) δ: fluorophenyl)-6-(2- 5-fluorophenyl)- spectroscopy: m/z 7.24 (ddd, J 9.2, 2.4, chloropyridin-4-yl)- 1,2,4-triazin-3-amine 336, 338 (M + H).sup.+ 1.4 Hz, 1H), 7.30 (dd, 1,2,4-triazin-3-amine (90 mg, 0.297 mmol), (ES.sup.+); 334, 336 (M − J 5.2, 1.4 Hz, 1H), (22 mg, 22%) 2-chloropyridin-4- H).sup.− (ES.sup.−), at 7.39 (t, J 1.4 Hz, 1H), ylboronic acid (53.7 4.27 min, 100% 7.53 (dd, J 1.4, 0.6 mg, 0.341 mmol) purity (method B). Hz, 1H), 7.59-7.65 (m, 1H), 7.85 (s, 2H), 8.38 (dd, J 5.2, 0.6 Hz, 1H). (cxlv) 6-(2-chloropyridin-4- 6-bromo-5-(3,5- Mass ((400 MHz, DMSO) δ: yl)-5-(3,5- difluorophenyl)-1,2,4- spectroscopy: m/z 7.11-7.24 (m, 2H), difluorophenyl)-1,2,4- triazin-3-amine (90 320, 322 (M + H).sup.+ 7.30 (dd, J 5.1, 1.4 triazin-3-amine (22 mg, 0.314 mmol), 2- (ES.sup.+); 318, 320 (M − Hz, 1H), 7.43 (tt, J mg, 22%) chloropyridin-4- H).sup.− (ES.sup.−), at 9.3, 2.4 Hz, 1H), 7.53 ylboronic acid (56.7 3.98 min, 98% purity (dd, J 1.4, 0.6 Hz, mg, 0.361 mmol) (method B) 1H), 7.84 (s, 2H), 8.38 (dd, J 5.1, 0.6 Hz, (cxlvi) 4-(3-amino-5-(4- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: (difluoromethoxy)phe- (difluoromethoxy)phe- spectroscopy: m/z 2.39 (s, 6H), 7.15- nyl)-1,2,4-triazin-6- nyl)-1,2,4-triazin-3- 368 (M + H).sup.+ (ES.sup.+); 7.21 (m, 2H), 7.24 (s, yl)-2,6- amine (90 mg, 0.284 366 (M − H).sup.− (ES.sup.−), at 2H), 7.31 (t, .sup.2J.sub.HF 72 dimethylbenzonitrile mmol), 2,6-dimethyl- 4.42 min, 99% purity Hz, 1H), 7.43-7.48 (32 mg, 30%) 4-(4,4,5,5- (method B). (m, 2H), 7.57 (s, 2H). tetramethyl-1,3,2- dioxaborolan-2- yl)benzonitrile (84 mg, 0.326 mmol) (cxlvii) 6-(2-chloro-6- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: methylpyridin-4-yl)-5- (difluoromethoxy)phe- spectroscopy: m/z 2.40 (s, 3H), 7.17 (s, (4- nyl)-1,2,4-triazin-3- 364, 366 (M + H).sup.+ 1H), 7.22 (d, J 8.7 (difluoromethoxy)phe- amine (90 mg, 0.284 (ES.sup.+); 362, 364 (M − Hz, 2H), 7.27 (d, J nyl)-1,2,4-triazin-3- mmol), 2-chloro-6- H).sup.− (ES.sup.−), at 0.7 Hz, 1H), 7.33 (t, amine (15 mg, 14%) methylpyridin-4- 4.14 min, 98% purity .sup.2J.sub.HF 72 Hz, 1H), 7.46- ylboronic acid (55.9 (method B). 7.51 (m, 2H), 7.71 mg, 0.326 mmol) (s, 2H). (cxlviii) 6-(2-chloropyridin-4- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: yl)-5-(4- (difluoromethoxy)phe- spectroscopy: m/z 7.21 (d, J 8.7 Hz, (difluoromethoxy)phe- nyl)-1,2,4-triazin-3- 350, 352 (M + H).sup.+ 2H), 7.29 (dd, J 5.2, nyl)-1,2,4-triazin-3- amine (90 mg, 0.284 (ES.sup.+); 348, 350 (M − 1.5 Hz, 1H), 7.34 (t, amine (17 mg, 17%) mmol), 2- H).sup.− (ES.sup.−), at 4.0 .sup.2J.sub.HF 72 Hz, 1H), 7.46- chloropyridin-4- min, 98% purity 7.55 (m, 3H), 7.73 ylboronic acid (51.4 (method B) (s, 2H), 8.35 (dd, J mg, 0.326 mmol) 5.2, 0.6 Hz, 1H). (cxlix) 6-(3-chloro-5- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: (trifluoromethyl)phe- (difluoromethoxy)phe- spectroscopy: m/z 7.17-7.23 (m, 2H), nyl)-5-(4- nyl)-1,2,4-triazin-3- 417, 419 (M + H).sup.+ 7.31 (t, .sup.2J.sub.HF 72 Hz, (difluoromethoxy)phe- amine (90 mg, 0.284 (ES.sup.+); 415, 417 (M − 1H), 7.44-7.50 (m, nyl)-1,2,4-triazin-3- mmol), 2-(3-chloro-5- H).sup.− (ES.sup.−), at 5.02 2H), 7.56-7.59 (m, amine (67 mg, 54%) (trifluoromethyl)phe- min, 95% purity 1H), 7.63 (s, 2H), nyl)-4,4,5,5- (method B). 7.74-7.75 (m, 1H), tetramethyl-1,3,2- 7.84-7.85 (m, 1H). dioxaborolane (87 mg, 0.284 mmol) (cl) 5-(3-amino-5-(3- 6-bromo-5-(3- Mass (400 MHz, DMSO) δ: fluorophenyl)-1,2,4- fluorophenyl)-1,2,4- spectroscopy: m/z 6.64 (dd, J 8.2, 2.0 triazin-6-yl)-2- triazin-3-amine (90 317, 319 (M + H).sup.+ Hz, 1H), 7.07 (d, J chlorophenol (16 mg, mg, 0.334 mmol), 4- (ES.sup.+); 315, 317 (M − 2.0 Hz, 1H), 7.23 (d, 15%) chloro-3- H).sup.− (ES.sup.−), at J 8.2 Hz, 1H), 7.34- hydroxyphenylboronic 2.68 min, 97% purity 7.48 (m, 7H), 10.26 acid (57.7 mg, (method B). (s, 1H). 0.334 mmol) (cli) 4-(3-amino-6-(3- 4-(3-amino-6-bromo- Mass (400 MHz, DMSO) δ: chloro-4- 1,2,4-triazin-5- spectroscopy: m/z 6.80-6.93 (m, 1H), hydroxyphenyl)- yl)benzonitrile (75 (Cl) 324.2/326.3 6.99 (dd, J 8.4, 2.2 1,2,4-triazin-5- mg, 0.272 mmol) and (M + H).sup.+ (ES+); Hz, 1H), 7.36 (d, J yl)benzonitrile (21 2-chloro-4-(4,4,5,5- 322.1/324.2 (M − H)− 2.2 Hz, 1H), 7.53- mg, 23%) tetramethyl-1,3,2- (ES−), at 2.48 min, 7.64 (m, 2H), 7.48 (s, dioxaborolan-2- 95.4% purity 2H), 7.84-7.93 (m, yl)phenol (76 mg, (method B). 2H), 10.44 (s, 1H). 0.299 mmol) (clii) 3-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 6.55-6.56 (m, 1H), (trifluoromethoxy)phe- (200 mg, 0.797 349 (M + H).sup.+ (ES.sup.+); 6.64-6.65 (m, 1H), nol (180 mg, 65%) mmol), 3-hydroxy-5- 347 (M − H).sup.− (ES.sup.−), at 6.87-6.91 (m, 1H), (trifluoromethoxy)phe- 3.22 min, 100% 7.31-7.53 (m, 7H), nylboronic acid (265 purity (method B). 10.15 (s, 1H). mg, 1.195 mmol) (cliii) 5-(3-chloro-5- 6-bromo-5-(3-chloro- Mass (400 MHz, DMSO) δ: fluorophenyl)-6-(2,6- 5-fluorophenyl)- spectroscopy: m/z 2.37 (s, 6H), 7.02 (s, dimethylpyridin-4-yl)- 1,2,4-triazin-3-amine 330(M + H).sup.+ (ES.sup.+); 2H), 7.18 (ddd, J = 1,2,4-triazin-3-amine (90 mg, 0.297 mmol), 328 (M − H).sup.− (ES.sup.−), at 9.3, 2.4, 1.4 Hz, 1H), (40 mg, 40%) 2,6-dimethyl-4- 4.27 min, 98% purity 7.36 (t, J 1.4 Hz, 1H), (4,4,5,5-tetramethyl- (method B). 7.56-7.61 (m, 1H), 1,3,2-dioxaborolan-2- 7.70 (s, 2H). yl)pyridine (79 mg, 0.341 mmol) (cliv) 5-(3,5- 6-bromo-5-(3,5- Mass (400 MHz, DMSO) δ: difluorophenyl)-6- difluorophenyl)-1,2,4- spectroscopy: m/z 2.37 (s, 6H), 7.01 (s, (2,6-dimethylpyridin- triazin-3-amine (90 314 (M + H).sup.+ (ES.sup.+); 2H), 7.04-7.16 (m, 4-yl)-1,2,4-triazin-3- mg, 0.314 mmol), 312 (M − H).sup.− (ES.sup.−), at 2H), 7.38-7.44 (m, amine (50 mg, 49%) 2,6-dimethyl-4- 3.95 min, 97% purity 1H), 7.70 (s, 2H). (4,4,5,5-tetramethyl- (method B) 1,3,2-dioxaborolan-2- yl)pyridine (84 mg, 0.361 mmol) (clv) 5-(3,4- 6-bromo-5-(3,4- Mass (400 MHz, DMSO) δ: difluorophenyl)-6- difluorophenyl)-1,2,4- spectroscopy: m/z 2.37 (s, 6H), 7.01 (s, (2,6-dimethylpyridin- triazin-3-amine (90 314(M + H).sup.+ (ES.sup.+); 2H), 7.15-7.23 (m, 4-yl)-1,2,4-triazin-3- mg, 0.314 mmol), 313 (M − H).sup.− (ES.sup.−), at 1H), 7.42-7.56 (m, amine 2,6-dimethyl-4- 3.97 min, 99% purity 2H), 7.65 (s, 2H). (4,4,5,5-tetramethyl- (method B). 1,3,2-dioxaborolan-2- yl)pyridine (84 mg, 0.361 mmol) (clvi) 5-(3-chloro-4- 6-bromo-5-(3-chloro- Mass (400 MHz, DMSO) δ: fluorophenyl)-6-(2,6- 4-fluorophenyl)- spectroscopy: m/z 2.37 (s, 6H), 7.02 (s, dimethylpyridin-4-yl)- 1,2,4-triazin-3-amine 330(M + H).sup.+ (ES.sup.+); 2H), 7.29 (ddd, J 8.6, 1,2,4-triazin-3-amine (90 mg, 0.297 mmol), 328 (M − H).sup.− (ES.sup.−), at 4.7, 2.2 Hz, 1H), 7.40- (38 mg, 38%) 2,6-dimethyl-4- 4.2 min, 97% purity 7.45 (m, 1H), 7.65 (4,4,5,5-tetramethyl- (method B). (s, 2H), 7.73 (dd, J 1,3,2-dioxaborolan-2- 7.2, 2.2 Hz, 1H). yl)pyridine (79 mg, 0.341 mmol) (clvii) 5-(4- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: (difluoromethoxy)phe- (difluoromethoxy)phe- spectroscopy: m/z 2.35 (s, 6H), 6.99 (s, nyl)-6-(2,6- nyl)-1,2,4-triazin-3- 344(M + H).sup.+ (ES.sup.+); 2H), 7.15-7.23 (m, dimethylpyridin-4-yl)- amine (90 mg, 0.284 342 (M − H).sup.− (ES.sup.−), at 2H), 7.32 (t, .sup.2J.sub.HF 72 1,2,4-triazin-3-amine mmol), 2,6-dimethyl- 3.93 min, 99% purity Hz, 1H), 7.43-7.49 (36 mg, 37%) 4-(4,4,5,5- (method B). (m, 2H), 7.58 (s, 2H). tetramethyl-1,3,2- dioxaborolan-2- yl)pyridine (76 mg, 0.326 mmol) (clviii) 6-(2,6- 6-bromo-5-(3- Mass (400 MHz, DMSO) δ: dimethylpyridin-4-yl)- fluorophenyl)-1,2,4- spectroscopy: m/z 2.36 (s, 6H), 7.02 (s, 5-(3-fluorophenyl)- triazin-3-amine (90 295.0 (M − H).sup.− (ES.sup.−), 2H), 7.17 (d, J 7.7 1,2,4-triazin-3-amine mg, 0.334 mmol) and at 3.82 min, 98.1% Hz, 1H), 7.25-7.36 (42 mg, 41%) 2,6-dimethyl-4- purity (method B). (m, 2H), 7.38-7.45 (4,4,5,5-tetramethyl- (m, 1H), 7.66 (s, 2H). 1,3,2-dioxaborolan-2- yl)pyridine (78 mg, 0.334 mmol) (clix) 5-(4-chlorophenyl)-6- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: (2,6-dimethylpyridin- chlorophenyl)-1,2,4- spectroscopy: m/z 2.39 (s, 6H), 7.07 (s, 4-yl)-1,2,4-triazin-3- triazin-3-amine (90 312.7/314.7 (M + H).sup.+ 2H), 7.41-7.51 (m, amine (33 mg, 34%) mg, 0.315 mmol) and (ES.sup.+); 310.9/312.9 4H), 7.67 (s, 2H). 2,6-dimethyl-4- (M − H).sup.− (ES.sup.−), at (4,4,5,5-tetramethyl- 4.17 min, 100% 1,3,2-dioxaborolan-2- purity (method B). yl)pyridine (73.5 mg, 0.315 mmol) (clx) 4-(3-amino-6-(2,6- 4-(3-amino-6-bromo- Mass (400 MHz, DMSO) δ: dimethylpyridin-4-yl)- 1,2,4-triazin-5- spectroscopy: m/z 2.36 (s, 6H), 7.01 (s, 1,2,4-triazin-5- yl)benzonitrile (90 303.8 (M + H).sup.+ 2H), 7.55-7.64 (m, yl)benzonitrile (27 mg, 0.326 mmol) and (ES.sup.+); 302.0 (M − H).sup.− 2H), 7.73 (s, 2H), mg, 27%) 2,6-dimethyl-4- (ES.sup.−), at 3.47 min, 7.85-7.95 (m, 2H). (4,4,5,5-tetramethyl- 98.5% purity 1,3,2-dioxaborolan-2- (method B). yl)pyridine (76 mg, 0.326 mmol) (clxi) 5-(3-chlorophenyl)-6- 6-bromo-5-(3- Mass (400 MHz, DMSO) δ: (2,6-dimethylpyridin- chlorophenyl)-1,2,4- spectroscopy: m/z 2.35 (s, 6H), 7.00 (s, 4-yl)-1,2,4-triazin-3- triazin-3-amine (90 312.7/314.7 (M + H).sup.+ 2H), 7.22-7.25 (m, amine (31 mg, 32%) mg, 0.315 mmol) and (ES.sup.+); 310.9/312.9 1H), 7.37 (dd, J 11.9, 2,6-dimethyl-4- (M − H).sup.− (ES.sup.−), at 4.2 Hz, 1H), 7.51- (4,4,5,5-tetramethyl- 4.10 min, 100% 7.60 (m, 2H), 7.65 (s, 1,3,2-dioxaborolan-2- purity (method B). 2H). yl)pyridine (73.5 mg, 0.315 mmol) (clxii) 6-(2,6- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: dimethylpyridin-4-yl)- (methoxymethyl)phe- spectroscopy: m/z 2.36 (s, 6H), 3.28 (s, 5-(4- nyl)-1,2,4-triazin-3- 322.7 (M + H).sup.+ 3H), 4.44 (s, 2H), (methoxymethyl)phe- amine (90 mg, 0.305 (ES.sup.+); 320.9 (M − H).sup.− 7.03 (s, 2H), 7.31- nyl)-1,2,4-triazin-3- mmol) and 2,6- (ES.sup.−), at 3.72 min, 7.34 (m, 2H), 7.37- amine (32 mg, 32%) dimethyl-4-(4,4,5,5- 98.5% purity 7.43 (m, 2H), 7.62 (s, tetramethyl-1,3,2- (method B). 2H). dioxaboralan-2- yl)pyridine (71.1 mg, 0.305 mmol) (clxiii) 4-(3-amino-6-(3- 4-(3-amino-6-bromo- Mass (400 MHz, DMSO) δ: chloro-4-hydroxy-5- 1,2,4-triazin-5- spectroscopy: m/z 3.60 (s, 3H), 6.81 (d, methoxyphenyl)- yl)benzonitrile (75 (Cl) 354.2/356.0 J 2.0 Hz, 1H), 6.92 1,2,4-triazin-5- mg, 0.272 mmol) and (M + H).sup.+ (ES.sup.+); (d, J 2.0 Hz, 1H), yl)benzonitrile (10 2-chloro-6-methoxy- 352.1/354.0 (M − H).sup.− 7.45 (s, 2H), 7.56- gm, 10%) 4-(4,4,5,5- (ES.sup.−), at 2.56 min, 7.64 (m, 2H), 7.84- tetramethyl-1,3,2- 94.6% purity 7.93 (m, 2H), 9.67 (s, dioxaborolan-2- (method B). 1H). yl)phenol (85 mg, 0.299 mmol) (clxiv) 5-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)-2- 1,2,4-triazin-3-amine spectroscopy: m/z 6.64 (dd, J = 8.2, 2.0 chlorophenol (43 mg, (90 mg, 0.358 mmol), 299, 301 (M + H).sup.+ Hz, 1H), 7.07 (d, J = 40%) 4-chloro-3- (ES.sup.+); 297, 299 (M − 2.0 Hz, 1H), 7.23 (d, hydroxyphenylboronic H).sup.− (ES.sup.−), at J = 8.2 Hz, 1H), 7.34- acid (61.8 mg, 2.55 min, 99% purity 7.47 (m, 7H), 10.26 0.358 mmol) (method B). (s, 1H). (clxv) 6-[2-chloro-6- 6-bromo-5-(3,4- Mass (400 MHz DMSO) (trifluoromethyl)pyridin- difluorophenyl)-1,2,4- spectroscopy: m/z δ: 7.25-7.32 (m, 1H), 4-yl]-5-(3,4- triazin-3-amine (115 387.84/389.77 7.48-7.57 (q, 1H), difluorophenyl)-1,2,4- mg, 0.40 mmol) [M + H].sup.+(ES).sup.+ 7.58-7.66 (m, 1H), triazin-3-amine and 2-chloro-4- 99.70% at 4.60 mnin 7.78(s, 1H), 7.82 (s, (20 mg, 13%) (4,4,5,5-tetramethyl- (method B). 1H), 7.93-7.99 (bs, 1,3,2-dioxaborolan-2- 2H) yl)-6- (trifluoromethyl)pyri- dine (129 mg, 0.421 mmol) (clxvi) 6-[2-chloro-6- 6-bromo-5-(3,5- Mass (400 MHz DMSO) (trifluoromethyl)pyridin- difluorophenyl)-1,2,4- spectroscopy: m/z δ: 7.20-7.25 (m, 2H), 4-yl]-5-(3,5- triazin-3-amine (115 387.87/389.78 7.46-7.51 (m, 1H), difluorophenyl)-1,2,4- mg, 0.40 mmol) [M + H]+ (ES).sup.+ 7.77 (s, 1H), 7.81 (s, triazin-3-amine and 2-chloro-4- 99.17% at 4.59 min 1H), 8.00 (bs, 2H) (26 mg, 17%) (4,4,5,5-tetramethyl- (method B). 1,3,2-dioxaborolan-2- yl)-6- (trifluoromethyl)pyridine (129 mg, 0.421 mmol) (clxvii) 6-[2-(ethylamino)-6- 6-bromo-5-phenyl- Mass (400 MHz DMSO) δ: methylpyridin-4-yl]-5- 1,2,4-triazin-3-amine spectroscopy: m/z 1.03 (t, 3H), 2.18 (s, phenyl-1,2,4-triazin- and 2-ethylamino-4- 307.1 3H), 3.94 (s, 2H), 3-amine (6 mg, (4,4,5,5-tetramethyl- [M + H]+ (ES).sup.+ 6.28 (s, 1H), 6.34 (s, 0.2%) 1,3,2-dioxaborolan-2- 93.7% at 1.024 min 1H) 7.37-7.50 (m, yl)-6-methylpyridine (method B). 5H). used crude from borylation step) (clxviii) 6-[2-chloro-6- 6-bromo-5-(3- Mass (400 MHz, DMSO) δ: (trifluoromethyl)pyridin- fluorophenyl)-1,2,4- spectroscopy: m/z 7.24 (d, J7.5 Hz, 1 4-yl]-5-(3- triazin-3-amine 370/372 (M + H).sup.+ H), 7.33-7.43 (m, 2 fluorophenyl)-1,2,4- (108 mg, 0.40 mmol) (ES.sup.+); 368/370 (M − H), 7.43-7.53 (m, 1 triazin-3-amine and 2-chloro-4- H).sup.− (ES.sup.−), at 3.83 H), 7.76 (s, 1 H), 7.79 (16 mg, 11%) (4,4,5,5-tetramethyl- min, (s, 1 H), 7.96 (bs, 2 1,3,2-dioxaborolan-2- 100% (method C). H). yl)-6- (trifluoromethyl)pyridine (129 mg, 0.42 mmol) (clxix) 6-[2-chloro-6- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: (trifluoromethyl)pyridin- fluorophenyl)-1,2,4- spectroscopy: m/z 7.23-7.41 (m, 2 H), 4-yl]-5-(4- triazin-3-amine 370/372 (M + H).sup.+ 7.46-7.65 (m, 2 H), fluorophenyl)-1,2,4- (108 mg, 0.40 mmol) (ES.sup.+); 368/370 (M − 7.76 (s, 1 H), 7.79 (1 triazin-3-amine and 2-chloro-4- H).sup.− (ES.sup.−), at 3.84 H, s), 7.90 (bs, 2 H). (13 mg, 9%) (4,4,5,5-tetramethyl- min, 1,3,2-dioxaborolan-2- 100% (method C). yl)-6- (trifluoromethyl)pyridine (129 mg, 0.42 mmol) (clxx) 6-{2- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: [ethyl(methyl)amino]- 1,2,4-triazin-3-amine spectroscopy: m/z 0.86 (t, J8 Hz, 3H) 6-methylpyridin-4-yl}- (126 mg, 0.5 mmol) 321 (M + H).sup.+ (ES.sup.+), 2.25 (s, 3 H) 2.81 (s, 5-phenyl-1,2,4- and 2- at 3.88 min, 3 H) 4.11 (q, J8 Hz, 2 triazin-3-amine (16 ethyl(methyl)amino- 100% (method C). H) 6.17 (s, 1 H) 6.49 mg, 10%) 4-(4,4,5,5- (s, 1 H) 7.32-7.47 tetramethyl-1,3,2- (m, 5 H) 7.50 (bs, 2 dioxaborolan-2-yl)-6- H). methylpyridine (276 mg, crude) (clxxi) 6-[2-(dimethylamino)- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 6-methylpyridin-4-yl]- 1,2,4-triazin-3-amine spectroscopy: m/z 2.24 (s, 3 H) 2.86 (s, 5-phenyl-1,2,4- (126 mg, 0.5 mmol) 307 (M + H).sup.+ (ES.sup.+), 6 H) 6.25 (s, 1 H) triazin-3-amine and crude 2- at 3.43 min, >99% 6.46 (s, 1 H) 7.34- (13 mg, 8%) dimethylamino-4- (method C). 7.47 (m, 5 H) 7.47- (4,4,5,5-tetramethyl- 7.57 (m, 2 H). 1,3,2-dioxaborolan-2- yl)-6-methylpyridine (234 mg, crude) (clxxii) 1-[6-(2,6-d.sub.6- 6-bromo-5-phenyl- Mass (400 MHz, CDCl.sub.3) δ: dimethylpyridin-4-yl)- 1,2,4-triazin-3-amine spectroscopy: m/z 5.49 (s, 2H), 7.02 (s, 5-phenyl-1,2,4- (310 mg, 1.24 mmol) 284.1 (M + H).sup.+ (ES.sup.+) 2H), 7.33-7.39 (m, triazin-3-amine and 1-[6-(2,6-d.sub.6- at 2.48 min, 100% 2H), 7.43-7.49 (m, (13.3 mg, 4%) dimethylpyridin-4-yl)- (method C). 3H). 5-phenyl-1,2,4- triazin-3-amine (crude, 1.17 g) (clxxiii) 6-[2-d.sub.3-methyl-6- 6-bromo-5-phenyl- Mass (400 MHz, CDCl.sub.3) δ: (trifluoromethyl)pyridin- 1,2,4-triazin-3-amine spectroscopy: m/z 5.57 (s, 2H), 7.37- 4-yl]-5-phenyl- (178 mg, 0.71 mmol) 335.1 (M + H).sup.+ 7.52 (m, 7H). 1,2,4-triazin-3-amine and 2-(d.sub.3)methyl-4- (ES.sup.+); 333.1 (M − H).sup.− (28.5 mg, 12%) (4,4,5,5-tetramethyl- (ES.sup.−) at 3.56 min, 1,3,2-dioxaborolan-2- 100% (method C). yl)-6- (trifluoromethyl)pyridine (226 mg, 0.78 mmol) (clxxiv) 5-(4-fluorophenyl)-6- 6-bromo-5-(4- Mass (400 MHz, CDCl.sub.3) δ: [2-d.sub.3-methyl-6- fluorophenyl)-1,2,4- spectroscopy: m/z 5.57 (s, 2H), 7.06- (trifluoromethyl)pyridin- triazin-3-amine 353.1 (M + H).sup.+ 7.12 (m, 2H), 7.45- 4-yl]-1,2,4-triazin- (189 mg, 0.70 mmol) (ES.sup.+); 351.1 (M − H).sup.− 7.50 (m, 3H), 7.51- 3-amine (93.3 mg, and 2-(d.sub.3)methyl-4- (ES.sup.−) at 3.68 min, 7.53 (m, 1H). 38%) (4,4,5,5-tetramethyl- 100% (method C). 1,3,2-dioxaborolan-2- yl)-6- (trifluoromethyl)pyridine (225 mg, 0.78 mmol) (clxxv) 6-(2,6- 6-bromo-5-(2- Mass (400 MHz, DMSO), δ: dimethylpyridin-4-yl)- fluoropheny)-1,2,4- spectroscopy: m/z 2.31 (s, 6H), 6.93 (s, 5-(2-fluorophenyl)- triazin-3-amine (50 296.0 (M + H).sup.+ 2H), 7.18 (t, J 7.8, 1,2,4-triazin-3-amine mg, 0.19 mmol) and (ES.sup.+), at 2.20 min, 1H), 7.37 (t, J 6.5, (32 mg, 57%) 2,6-dimethyl-4- 100% (method C). 1H), 7.54-7.66 (m, (4,4,5,5-tetramethyl- 6H) 1,3,2-dioxaborolan-2- yl)-pyridine (68 mg, 0.29 mmol) (clxxvi) 6-(2-chloro-6- 6-bromo-5-(2- Mass (400 Mhz, DMSO) methylpyridin-4-yl)-5- fluoropheny)-1,2,4- spectroscopy: m/z δ: 2.31 (s, 3H), 7.06 (2-fluorophenyl)- triazin-3-amine (50 315.9 (M + H).sup.+ (s, 1H). 7.21 (t, J 7.8, 1,2,4-triazin-3-amine mg, 0.19 mmol) and (ES.sup.+), at 2.66 min, 1H), 7.27 (s, 1H), (21 mg, 35%) 2-chloro-4-(4,4,5,5- 100% (method C). 7.40 (t, J 6.5, 1H), tetramethyl-1,3,2- 7.56-7.63 (m, dioxaborolan-2-yl)-6- 1H), 7.64-7.69 (m, methylpyridine (74 1H), 7.80-7.90 (bs, mg, 0.29 mmol) 2H) (clxxvii) 6-(2,6- 6-bromo-5-(4- Mass (400 MHz, DMSO) dimethylpyridin-4-yl)- methoxypheny)- spectroscopy: m/z δ: 2.37 (s, 6H), 3.78 5-(4-methoxyphenyl)- 1,2,4-triazin-3-amine 308.0 (M + H).sup.+ (s, 3H), 6.95 (d, J 9.0, 1,2,4-triazin-3-amine (50 mg, 0.18 mmol) (ES.sup.+), at 2.31 min, 2H), 7.02 (s, 2H), (20 mg, 36%) and 2,6-dimethyl-4- 100% (method C). 7.39 (d, J 9.0, 2H), (4,4,5,5-tetramethyl- 7.45-7.55 (bs, 2H) 1,3,2-dioxaborolan-2- yl)-pyridine (63 mg, 0.27 mmol) (clxxviii) 6-(2-chloro-6- 6-bromo-5-(4- Mass (400 MHz, DMSO) methylpyridin-4-yl)-5- methoxypheny)- spectroscopy: m/z δ: 2.42 (s, 3H), 3.80 (4-methoxyphenyl)- 1,2,4-triazin-3-amine 328.0 (M + H).sup.+ (s, 3H) 6.98 (d, J 8.8, 1,2,4-triazin-3-amine (50 mg, 0.18 mmol) (ES.sup.+), at 2.72 min, 2H), 7.18 (s, 1H), (10 mg, 17%) and 2-chloro-4- 100% (method C). 7.31 (s, 1H), 7.41 (d, (4,4,5,5-tetramethyl- J 8.8, 2H), 7.37-7.43 1,3,2-dioxaborolan-2- (s, 2H) yl)-6-methylpyridine (68 mg, 0.27 mmol) (clxxix) 6-[2-(difluoromethyl)- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) 6-methylpyridin-4-yl]- 1,2,4-triazin-3-amine spectroscopy: m/z δ: 2.46 (s, 3H), 6.83 5-phenyl-1,2,4- (100 mg, 0.40 mmol) 314.1 (M + H).sup.+ (t, J 55.0, 1H), 7.33 triazin-3-amine (42 and (2- (ES.sup.+), at 1.38 min, (s, 1H), 7.38-7.45 (m, mg, 32%) (difluoromethyl)-4- 100% (method A). 5H), 7.47-7.52 (m, (4,4,5,5-tetramethyl- 1H), 7.62-7.75 (bs, 1,3,2-dioxaborolan-2- 2H) yl)-6-methylpyridine (108 mg, 0.40 mmol) (clxxx) 6-[2-chloro-6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) (difluoromethyl)pyridin- 1,2,4-triazin-3-amine spectroscopy: m/z δ: 6.94 (t, J 54.5, 1H), 4-yl]-5-phenyl- (100 mg, 0.40 mmol) 333.9 (M + H).sup.+ 7.41-7.48(m, 4H), 1,2,4-triazin-3-amine and 2-chloro-4- (ES.sup.+), at 1.56 min, 7.50-7.56 (m, 1H), (27 mg, 20%) (4,4,5,5-tetramethyl- 100% (method C). 7.57 (s, 1H), 7.62 (s, 1,3,2-dioxaborolan-2- 1H) yl)-6-(difluoromethyl)- pyridine (151 mg, 0.52 mmol) (clxxxi) 6-[2-chloro-6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) (fluoromethyl)pyridin- 1,2,4-triazin-3-amine spectroscopy: m/z δ: 5.43 (d, J 46.4, 2H), 4-yl]-5-phenyl-1,2,4- (100 mg, 0.40 mmol) 316.0 (M + H).sup.+ 7.33 (s, 1H), 7.41- triazin-3-amine (13 and 2-chloro-4- (ES.sup.+), at 3.12 min, 7.46 (m, 5H), 7.47- mg, 10%) (4,4,5,5-tetramethyl- 100% (method C). 7.53 (m, 3H) 1,3,2-dioxaborolan-2- yl)-6-(fluoromethyl)- pyridine (141 mg, 0.52 mmol) (clxxxii) 6-[2-(difluoromethyl)- 6-bromo-5-(4- Mass (400 MHz, DMSO) 6-methylpyridin-4-yl]- fluorophenyl)-1,2,4- spectroscopy: m/z δ: 2.49(s, 3H), 6.82 5-(4-fluorophenyl)- triazin-3-amine (100 332.0 (M + H).sup.+ (t, J 55.0 Hz, 1H), 1,2,4-triazin-3-amine mg, 0.37 mmol) and (ES.sup.+), at 1.42 min, 7.19-7.31 (m, 1H), (32 mg, 26%) (2-(difluoromethyl-4- 100% (method A). 7.36 (s, 1H), 7.44 (s, (4,4,5,5-tetramethyl- 1H), 7.46-7.52 (m, 1,3,2-dioxaborolan-2- 2H), 7.54-7.58 (, 2H) yl)-6-methylpyridine (110 mg, 0.41 mmol) (clxxxiii) 6-[2,6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: bis(fluoromethyl)pyri- 1,2,4-triazin-3-amine spectroscopy: m/z 5.43 (d, J 46.9 Hz, dine-4-yl]-5-phenyl- (100 mg, 0.40 mmol) 314.0 (M + H).sup.+ 4H), 7.38-7.45 (m, 1,2,4-triazin-3-amine and 2,6-bis- (ES.sup.+), at 1.33 min, 6H), 7.47-7.51 (m, (10 mg, 8%) (fluoromethyl-4- 95% (method A). 1H), 7.65-7.75(bs, (4,4,5,5-tetramethyl- 2H). 1,3,2-dioxaborolan-2- yl)-6-methylpyridine (140 mg, 0.52 mmol) (clxxxiv) 6-[2-(fluoromethyl)-6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) methylpyridin-4-yl]-5- 1,2,4-triazin-3-amine spectroscopy: m/z δ: 2.40(s, 3H), 5.37 phenyl-1,2,4-triazin- (100 mg, 0.40 mmol) 296.0 (M + H).sup.+ (d, J 46.9 Hz, 2H), 3-amine (10 mg, 8%) and (2-(fluoromethyl- (ES.sup.+), at 2.58 min, 7.20 (s, 2H), 7.38- 4-(4,4,5,5- 100% (method C). 7.45 (m, 4H), 7.46- tetramethyl-1,3,2- 7.51 (m, 1H), 7.60- dioxaborolan-2-yl)-6- 7.72 (bs, 2H) methylpyridine (151 mg, 0.60 mmol) (clxxxv) 6-(2-chloro-6- 6-bromo-5-(2,5- Mass (400 MHz, DMSO) δ: methylpyridin-4-yl)-5- difluorophenyl)-1,2,4- spectroscopy: m/z 2.40 (s, 3H), 7.12 (s, (2,5-difluorophenyl)- triazin-3-amine (115 334.0 (M + H).sup.+ 1H), 7.25-7.32 (m, 1,2,4-triazin-3-amine mg, 0.40 mmol) and (ES+); at 2.87 min, 2H), 7.42-7.49 (m, (24 mg, 18%) 2-chloro-4-(4,4,5,5- 95% (method C). 1H), 7.51-7.56 (m, tetramethyl-1,3,2- 1H), 7.89 (br s, 2H). dioxaborolan-2-yl)-6- methylpyridine(129 mg, 0.42 mmol) (clxxxvi) 6-[2-chloro-6- 6-bromo-5-(2- Mass (400 MHz, DMSO) δ: (trifluoromethyl)pyridin- fluorophenyl)-1,2,4- spectroscopy: m/z 7.20-7.26 (m, 1H), 4-yl]-5-(2- triazin-3-amine (108 368.1(M + H).sup.+ (ES+), 7.38-7.45 (m, 1H), fluorophenyl)-1,2,4- mg, 0.40 mmol) and 370 (M − H).sup.− (ES−); 7.56-7.74 (m, 3H), triazin-3-amine 2-chloro-4-(4,4,5,5- at 3.85 min, 95% 7.78 (s, 1H). (18 mg, 12%) tetramethyl-1,3,2- (method C). dioxaborolan-2-yl)-6- (trifluoromethyl)pyridine (129 mg, 0.42 mmol) (clxxxvii) 6-[2-chloro-6- 6-bromo-5-(2,5- Mass (400 MHz, DMSO) δ: (trifluoromethyl)pyridin- difluorophenyl)-1,2,4- spectroscopy: m/z 7.27-7.35 (m, 1H), 4-yl]-5-(2,5- triazin-3-amine (115 386.1(M − H).sup.− (ES−); 7.45-7.52 (m, 1H), difluorophenyl)-1,2,4- mg, 0.40 mmol) and at 3.93 min, 95% 7.52-7.58 (m, 1H), triazin-3-amine 2-chloro-4-(4,4,5,5- (method C). 7.79 (s, 1H), 7.82 (s, (17 mg, 11%) tetramethyl-1,3,2- 1H), 8.08 (bs, 2H). dioxaborolan-2-yl)-6- (trifluoromethyl)pyridine (129 mg, 0.42 mmol) (clxxxviii) 6-[2-cyclopropyl-6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethyl)pyridin- 1,2,4-triazin-3-amine spectroscopy: m/z 0.79-0.84 (m, 2H), 4-yl]-5-phenyl- (50 mg, 0.20 mmol) 358 (M + H).sup.+ (ES+); 0.97-1.03 (m, 2H), 1,2,4-triazin-3-amine and 2-cyclopropyl-4- at 4.43 min, 100% 2.10-2.17 (m, 1H), (20 mg, 26%) (4,4,5,5-tetramethyl- (method C). 7.39-7.46 (m, 6H), 1,3,2-dioxaborolan-2- 7.47-7.53 (m, 1H), yl)-6- 7.61 (bs, 2H). (trifluoromethyl)pyridine (66 mg, 0.21 mmol) (clxxxix) 6-[2-ethyl-6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethyl)pyridin- 1,2,4-triazin-3-amine spectroscopy: m/z 1.10 (t, 3H, J8.0 Hz), 4-yl]-5-phenyl- (50 mg, 0.20 mmol) 346.0 (M + H).sup.+ 2.75 (q, 2H, J 8.0), 1,2,4-triazin-3-amine and 2-ethyl-4- (ES+), 344.2 (M − H).sup.− 7.40-7.44 (m, 4H), (37 mg, 55%) (4,4,5,5-tetramethyl- (ES−) at 4.08 min, 7.47-7.53 (m, 2H). 1,3,2-dioxaborolan-2- 100% (method C). 7.57 (s, H), 7.76 (bs, yl)-6- 2H). (trifluoromethyl)pyridine (63 mg, 0.21 mmol) (cxc) 6-(2-cyclopropyl-6- 6-(2-chloro-6- Mass (400 MHz, DMSO) δ: methylpyridin-4-yl)-5- methylpyridin-4-yl)-5- spectroscopy: m/z 0.70-0.76 (m, 2H), phenyl-1,2,4-triazin- phenyl-1,2,4-triazin- 304.1 (M + H).sup.+ 0.82-0.89 (m, 2H), 3-amine 3-amine (70 mg, 0.23 (ES+); at 3.22 min, 1.88-1.97 (m, 1H), (32 mg, 46%) mmol) and 100% (method C). 2.32 (s, 3H), 6.88 (s, cyclopropyltrifluoro- 1H), 6.97 (s, 1H), borate potassium salt 7.38-7.43 (m, 4H), (340 mg, 2.30 mmol) 7.45-7.52 (m, 1H), 7.54-7.62 (bs, 2H). (cxci) 5-(2-fluorophenyl)-6- 6-bromo-5-(2- Mass (400 MHz, DMSO) δ: [2-methyl-6- fluorophenyl)-1,2,4- spectroscopy: m/z 2.51 (s, 3H), 7.17- (trifluoromethyl)pyridin- triazin-3-amine (108 350.0 (M + H).sup.+ (ES.sup.+) 7.22 (m, 1H), 7.38- 4-yl]-1,2,4-triazin- mg, 0.40 mmol) and at 3.30 min, 7.42 (m, 2H), 7.56- 3-amine (65.3 mg, 2-methyl-6- ~98% (method C). 7.63 (m, 2H), 7.67- 47%) trifluoromethyl-4- 7.71 (m, 1H), 7.88 (4,4,5,5-tetramethyl- (bs, 2H). 1,3,2-dioxaborolan-2- yl)pyridine (121 mg, 0.42 mmol) (cxcii) 5-(3-fluorophenyl)-6- 6-bromo-5-(3- Mass (400 MHz, CDCl.sub.3) [2-methyl-6- fluorophenyl)-1,2,4- spectroscopy: m/z δ: 2.61 (s, 3H), 5.62 (trifluoromethyl)pyridin- triazin-3-amine (108 350.0 (M + H).sup.+ (ES.sup.+) (bs, 2H), 7.10- 4-yl]-1,2,4-triazin- mg, 0.40 mmol) and at 3.24 min, 7.20 (m, 1H), 7.18- 3-amine (72.8 mg, 2-methyl-6- ~98% (method C). 7.23 (m, 1H), 7.28- 52%) trifluoromethyl-4- 7.35 (m, 2H), 7.48- (4,4,5,5-tetramethyl- 7.50 (m, 2H). 1,3,2-dioxaborolan-2- yl)pyridine (121 mg, 0.42 mmol) (cxciii) 5-(4-fluorophenyl)-6- 6-bromo-5-(4- Mass (400 MHz, CDCl.sub.3) [2-methyl-6- fluorophenyl)-1,2,4- spectroscopy: m/z δ: 2.61 (s, 3H), 5.58 (trifluoromethyl)pyridin- triazin-3-amine (108 350.0 (M + H).sup.+ (ES.sup.+) (bs, 2H), 7.07- 4-yl]-1,2,4-triazin- mg, 0.40 mmol) and at 3.26 min, 7.11 (m, 2H), 7.46- 3-amine (78.9 mg, 2-methyl-6- 98% (method C). 7.52 (m, 4H). 56%) trifluoromethyl-4- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)pyridine (121 mg, 0.42 mmol) (cxciv) 5-(2,5- 6-bromo-5-(2,5- Mass (400 MHz, DMSO) δ: difluorophenyl)-6-[2- difluorophenyl)-1,2,4- spectroscopy: m/z 2.53 (s, 3H), 7.25- methyl-6- triazin-3-amine (115 368.0 (M + H).sup.+ (ES.sup.+) 7.30 (m, 1H), 7.44- (trifluoromethyl)pyridin- mg, 0.40 mmol) and at 3.38 min, 7.50 (m, 2H), 7.55- 4-yl]-1,2,4-triazin- 2-methyl-6- 98% (method C). 7.59 (m, 1H), 7.65 (s, 3-amine (61.7 mg, trifluoromethyl-4- 1H), 7.95 (bs, 2H). 42%) (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)pyridine (121 mg, 0.42 mmol) (cxcv) 5-(3,4- 6-bromo-5-(3,4- Mass (400 MHz, DMSO) δ: difluorophenyl)-6-[2- difluorophenyl)-1,2,4- spectroscopy: m/z 2.54 (s, 3H), 7.22- methyl-6- triazin-3-amine (115 368.0 (M + H).sup.+ (ES.sup.+) 7.24 (m, 1H), 7.46- (trifluoromethyl)pyridin- mg, 0.40 mmol) and at 4.34 min, 7.57 (m, 3H), 7.62 (s, 4-yl]-1,2,4-triazin- 2-methyl-6- 100% (method B). 1H), 7.81 (bs, 2H). 3-amine (40.0 mg, trifluoromethyl-4- 27%) (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)pyridine (121 mg, 0.42 mmol) (cxcvi) 5-(3,5- 6-bromo-5-(3,5- Mass (400 MHz, DMSO) δ: difluorophenyl)-6-[2- difluorophenyl)-1,2,4- spectroscopy: m/z 2.54 (s, 3H), 7.16- methyl-6- triazin-3-amine (115 368.0 (M + H).sup.+ (ES.sup.+) 7.19 (m, 2H), 7.42- (trifluoromethyl)pyridin- mg, 0.40 mmol) and at 3.53 min, 7.49 (m, 2H), 7.64 (s, 4-yl]-1,2,4-triazin- 2-methyl-6- ~98% (254 nm). 1H), 7.81 (bs, 2H). 3-amine (73.3 mg, trifluoromethyl-4- 49%) (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)pyridine (121 mg, 0.42 mmol) (cxcvii) 6-[2-(azetidin-1-yl)-6- 6-bromo-5-(4- Mass (400 MHz, CDCl.sub.3) (trifluoromethyl)pyridin- fluorophenyl)-1,2,4- spectroscopy: m/z δ: 2.27-2.35 4-yl]-5-(4- triazin-3-amine (150 391.0 (M + H).sup.+ (ES.sup.+) (quint., J 7.4, 2H), fluorophenyl)-1,2,4- mg, 0.56 mmol) and at 3.89 min, 3.89 (t, J 7.4, 4H), triazin-3-amine 2-(azetid-1-yl)-6- ~98% (method C). 5.52 (bs, 2H), 6.54 (40.2 mg, 18%) trifluoromethyl-4- (s, 1H), 6.83 (s, 1H), (4,4,5,5-tetramethyl- 7.06-7.10 (m, 2H), 1,3,2-dioxaborolan-2- 7.49-7.53 (m, 2H). yl)pyridine (192 mg, 0.59 mmol) (cxcviii) 6-[2-methyl-6- 6-bromo-5-phenyl- Mass (400 MHz, CDCl.sub.3) (morpholin-4- 1,2,4-triazin-3-amine spectroscopy: m/z δ: 2.33 (s, 3H), 3.39- yl)pyridin-4-yl]-5- (251 mg, 1.0 mmol) 349.1 (M + H).sup.+ (ES.sup.+) 3.42 (m, 2H), 3.76- phenyl-1,2,4-triazin- and 2-methyl-6- at 1.16 min, 3.78 (m, 2H), 5.49 3-amine (43.0 mg, (morpholin-4-yl)-4- ~95% (method B). (bs, 2H), 6.52 (s, 12%) (4,4,5,5-tetramethyl- 1H), 6.55 (s, 1H), 1,3,2-dioxaborolan-2- 7.34-7.38 (m, 2H), yl)pyridine (320 mg, 7.43-7.45 (m, 1H), 1.05 mmol) 7.50-7.52 (m, 2H). (cxcix) 6-(2-chloro-6- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: methylpyridin-4-yl)-5- methylphenyl)-1,2,4- spectroscopy: m/z 1.18 (t, 3H), 2.40 (s, (4-ethylphenyl)-1,2,4- triazin-3-amine (94 324.2 (M − H).sup.− (ES−) 3H), 2.64 (q, 2H), triazin-3-amine (6 mg, crude - assume at 2.16 min, 97% 7.22 (s, 1H), 7.55 (m, mg, 6%) 0.17 mmol) and 2- (method B) 3H), 7.38 (m, 2H) chloro-4-(4,4,5,5- (NH.sub.2 not observed) tetramethyl-1,3,2- dioxaborolan-2-yl)-6- methylpyridine (128 mg, 0.506 mmol) (cc) 5-(2,5- 6-bromo-5-(2,5- Mass (400 MHz, DMSO) δ: difluorophenyl)-6- difluorophenyl)- spectroscopy: m/z 2.34 (s, 6H), 6.98 (s, (2,6-dimethylpyridin- 1,2,4-triazin-3-amine 314.3 (M + H).sup.+ (ES+) 2H), 7.26 (m, 1H), 4-yl)-1,2,4-triazin-3- (90 mg, 0.314 mmol) at 0.97 min, 100% 7.44 (m, 1H), 7.54 amine (12 mg, 12%) and 2,6-dimethyl-4- (method B) (m, 1H), 1.78 (bs, 2H) (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)pyridine (110 mg, 0.47 mmol) (cci) 6-(2,6- 6-bromo-5-(4- Mass (400 MHz, DMSO) δ: dimethylpyridin-4-yl)- methylphenyl)-1,2,4- spectroscopy: m/z 2.31 (s, 3H), 2.36 (s, 5-(4-methylphenyl)- triazin-3-amine (85 293.3 (M + H).sup.+ (ES+) 6H), 6.99 (s, 2H), 1,2,4-triazin-3-amine mg, 0.32 mmol) and at 1.06 min, 99% 7.20 (m, 2H), 7.33 (16 mg, 17%) 2,6-dimethyl-4- (method B) (m, 2H), 7.53 (bs, (4,4,5,5-tetramethyl- 2H). 1,3,2-dioxaborolan-2- yl)pyridine (112 mg, 0.48 mmol) (ccii) 6-[2-(difluoromethyl)- 6-bromo-5-(3- Mass (400 MHz, CDCl.sub.3) 6-methylpyridin-4-yl]- fluorophenyl)-1,2,4- spectroscopy: m/z δ: 2.51 (s, 3H), 5.51 5-(3-fluorophenyl)- triazin-3-amine (70 332.3, M.sup.+ (ESI+) at (bs, 2H), 6.55 (t, 1H), 1,2,4-triazin-3-amine mg, 0.26 mmol) and 1.84 min, 96% 7.13 (m, 1H), 7.29 (17 mg, 20%) (2-(difluoromethyl-4- (method B). (m, 1H), 7.32 (m, 1H), (4,4,5,5-tetramethyl- 7.40 (s, 1H), 7.44 (s, 1,3,2-dioxaborolan-2- 1H) yl)-6-methylpyridine (70 mg, 0.26 mmol) (cciii) 6-[2-(difluoromethyl)- 6-bromo-5-(3- Mass (400 MHz, CDCl.sub.3) 6-methylpyridin-4-yl]- fluorophenyl)-1,2,4- spectroscopy: m/z δ: 2.55 (s, 3H), 5.54 5-(2-fluorophenyl)- triazin-3-amine (70 332.3, M.sup.+ (ESI+) at (bs, 2H), 6.51 (t, 1H), 1,2,4-triazin-3-amine mg, 0.26 mmol)and 1.80 min, 96% 7.00 (m, 1H), 7.30 (s, (20 mg, 23%) (2-(difluoromethyl-4- (method B). 1H) 7.32 (m, 1H), (4,4,5,5-tetramethyl- 7.43 (s, 1H), 7.50 (m, 1,3,2-dioxaborolan-2- 1H), 7.58 (m, 1H). yl)-6-methylpyridine (70 mg, 0.26 mmol) (cciv) 6-(3,5- 6-bromo-5-(pyridin-2- HPLC purity: (400 MHz, DMSO) δ: dichlorophenyl)-5- yl)-1,2,4-triazin-3- 98.56%; (268 nm). 7.26 (m, 2H), 7.49 (pyridin-2-yl)-1,2,4- amine (0.25 g, 0.99 Mass (m, 1H), 7.54 (m, 1H), triazin-3-amine (23 mmol) and 3,5- spectroscopy: 7.68 (bs, 2H), 7.91 mg, 7%) dichlorophenylboronic (ESI +ve) 318.0 (m, 1H), 8.00 (t, 1H), acid (0.20 g, 1.09 [M + H].sup.+, 316.1 8.43 (d, 1H). mmol) [M + H].sup.−. (ccv) 6-(3-chloro-5- 6-bromo-5-(pyridin-2- HPLC purity: (400 MHz, DMSO) δ: methylphenyl)-5- yl)-1,2,4-triazin-3- 99.60%; (266 nm). 2.22 (s, 3H), 6.99 (s, (pyridin-2-yl)-1,2,4- amine (0.20 g, 0.79 Mass 1H), 7.07 (s, 1H), triazin-3-amine (12 mmol) and 3-chloro- spectroscopy: 7.18 (s, 1H), 7.45- mg, 5%) 5-methylphenyl- (ESI +ve) 298.2 7.48 (m, 1H), 7.56 boronic acid (0.175 [M + H].sup.+. (bs, 2H), 7.79 (d, 1H), g, 1.03 mmol) 7.94-7.98 (m, 1H), 8.44 (d, 1H). (ccvi) 6-[2-chloro-6- 6-bromo-5-phenyl- HPLC purity: .sup.1H NMR: (400 MHz, (trifluoromethyl)pyridin- 1,2,4-triazin-3-amine 96.75% (272 nm) DMSO) δ: 7.44 (m, 4-yl]-5-phenyl- (0.70 g, 2.8 mmol) Mass 5H), 7.69 (s, 1H), 1,2,4-triazin-3-amine and 2-chloro-4- spectroscopy: 7.88 (s, 1H), 7.84 (bs, (50 mg, 5%) (4,4,5,5-tetramethyl- (ESI +ve) 352.1 2H). 1,3,2-dioxaborolan-2- [M + H].sup.+. yl)-6- (trifluoromethyl)pyridine (1.02 g, 3.34 mmol) (ccvii) 6-[2,6- 6-bromo-5-phenyl- HPLC purity: .sup.1H NMR: (400 MHz, bis(trifluoromethyl)pyr- 1,2,4-triazin-3-amine 98.90% (232 nm) DMSO) δ: 7.48 (m, idin-4-yl]-5-phenyl- (0.52 g, 2.07 mmol) Mass 5H), 7.93 (bs, 2H), 1,2,4-triazin-3-amine and 2,6- spectroscopy: 8.03 (s, 2H). (0.10 g, 13%) bis(trifluoromethyl)-4- (ESI +ve) (4,4,5,5-tetramethyl- 386.1[M + H].sup.+, (ESI −ve) 1,3,2-dioxaborolan-2- 384.2[M − H].sup.−. yl)pyridine (1.0 g, 3.1 mmol) (ccviii) 6-[3-chloro-5- 6-bromo-5-(pyridin-2- HPLC purity: (400 MHz, DMSO) δ: (trifluoromethyl)phe- yl)-1,2,4-triazin-3- 99.87%; (268 nm). 7.45-7.48 (m, 2H), nyl]-5-(pyridin-2-yl)- amine (0.225 g, 0.89 Mass 7.65 (s, 1H), 7.70 (bs, 1,2,4-triazin-3-amine mmol) and 3-chloro- spectroscopy: 2H), 7.77 (s, 1H), (30 mg, 10%) 5-(trifluoromethyl)- (ESI +ve) 352.1 7.91 (m, 1H), 8.0 (m, phenylboronic acid [M + H].sup.+. 1H), 8.36 (d, 1H). (0.260 g, 1.16 mmol) (ccix) 6-[2-methyl-6- 6-bromo-5-phenyl- HPLC purity: (400 MHz, DMSO) δ: (trifluoromethyl)pyridin- 1,2,4-triazin-3-amine 98.81% (269 nm) 2.48 (s, 3H), 7.38 (m, 4-yl]-5-phenyl- (0.70 g, 2.78 mmol) Mass 5H), 7.47 (s, 1H), 1,2,4-triazin-3-amine and 2-methyl-4- spectroscopy: 7.58 (s, 1H), 7.73 (bs, (0.32 g, 35%) (4,4,5,5-tetramethyl- (ESI +ve) 332.0 2H). 1,3,2-dioxaborolan-2- [M + H].sup.+, (ESI −ve) yl)-6-trifluoromethyl- 330.2 [M − H].sup.−. pyridine (1.2 g, 4.1 mmol) (ccx) 6-(3,5- 6-bromo-5-(pyridin-2- HPLC purity: (400 MHz, DMSO) δ: dimethylphenyl)-5- yl)-1,2,4-triazin-3- 98.96%; (268 nm). 2.12 (s, 6H), 6.81 (s, (pyridin-2-yl)-1,2,4- amine (0.20 g, 0.79 Mass 2H), 6.88 (s, 1H), triazin-3-amine (16 mmol) and 3,5- spectroscopy: 7.40-7.43 (m, 3H), mg, 7%) dimethylphenylboronic (ESI +ve) 277.9 7.64-7.66 (m, 1H), acid (0.15 g, 1.02 [M + H].sup.+. 7.89 (m, 1H), 8.43 mmol) (m, 1H). (ccxi) 6-[2- 6-bromo-5-phenyl- HPLC purity: (400 MHz, DMSO) δ: (dimethylamino)pyridin- 1,2,4-triazin-3-amine 99.18% (272 nm) 2.97 (s, 6H), 6.46 (m, 4-yl]-5-phenyl- (0.5 g, 1.99 mmol) Mass 1H), 6.56 (m, 1H), 1,2,4-triazin-3-amine and 2- spectroscopy: 7.37-7.47 (m, 5H), (83 mg, 33%) dimethylamino- (ESI +ve) 292.8 7.54 (bs, 2H), 7.99 (4,4,5,5-tetramethyl- [M + H].sup.+. (m, 1H). 1,3,2-dioxaborolan-2- yl)pyridine (0.98 g, 3.9 mmol) (ccxii) 6-(2-bromo-6- 6-bromo-5-phenyl- HPLC purity: (400 MHz, DMSO) δ: methylpyridin-4-yl)-5- 1,2,4-triazin-3-amine 98.71% (272 nm) 2.38 (s, 3H), 7.25 (s, phenyl-1,2,4-triazin- (0.25 g, 0.90 mmol) Mass 1H), 7.30 (s, 1H), 3-amine (76 mg, and 2-bromo-4- spectroscopy: 7.47 (m, 5H), 7.72 22%) (4,4,5,5-tetramethyl- (ESI +ve) 341.9 [M].sup.+, (bs, 2H). 1,3,2-dioxaborolan-2- 343.9 [M].sup.+. yl)-6-methylpyridine (0.44 g, 1.4 mmol) (ccxiii) 6-(2,6-dimethyl-1- 6-bromo-5-phenyl- HPLC purity: (400 MHz, CDCl.sub.3) δ: oxidopyridin-4-yl)-5- 1,2,4-triazin-3-amine 98.85% (294 nm) 2.48 (s, 6H), 5.66 (bs, phenyl-1,2,4-triazin- (0.50 g, 1.99 mmol) Mass 2H), 7.24 (s, 1H), 3-amine (87 mg, and 2,6-dimethyl-4- spectroscopy: 7.28 (s, 1H), 7.49 (m, 15%) (4,4,5,5-tetramethyl- (ESI +ve) 293.7 2H), 7.52 (m, 3H). 1,3,2-dioxaborolan-2- [M + H] .sup.+, (ESI −ve) yl)pyridine-N-oxide 292.0 [M − H].sup.−. (0.74 g, 2.98 mmol) (ccxiv) 4-(3-amino-5-phenyl- 6-bromo-5-phenyl- HPLC purity: (400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)-6- 1,2,4-triazin-3-amine 99.18% (272 nm) 2.48 (s, 3H), 7.45- methylpyridine-2- (0.25 g, 0.99 mmol) Mass 7.52 (m, 5H), 7.61 (s, carbonitrile (140 mg, and 2-cyano-4- spectroscopy: 1H), 7.63 (s, 1H), 49%) (4,4,5,5-tetramethyl- (ESI +ve) 288.9 7.79 (bs, 2H). 1,3,2-dioxaborolan-2- [M + H].sup.+. yl)-6-methylpyridine (0.36 g, 1.4 mmol) (ccxv) 6-(3,5- 6-bromo-5-(pyridin-3- HPLC purity: (400 MHz, DMSO) δ: dichlorophenyl)-5- yl)-1,2,4-triazin-3- 98.66% (266 nm) 7.39 (m, 2H), 7.42- (pyridin-3-yl)-1,2,4- amine (0.3 g, 1.19 Mass 7.46 (m, 1H), 7.62 triazin-3-amine (3 mmol) and 3,5- spectroscopy: (m, 1H), 7.69 (bs, mg, 1%) dichlorophenylboronic (ESI +ve) 317.9 2H), 7.82 (m, 1H), acid (0.22 g, 1.19 [M + H].sup.+. 315.9 8.59 (m, 1H), 8.63 mmol) [M + H].sup.− (m, 1H). (ccxvi) 6-(3-chloro-5- 6-bromo-5-(pyridin-3- HPLC purity: (400 MHz, DMSO) δ: methylphenyl)-5- yl)-1,2,4-triazin-3- 92.24% (218 nm) 2.25 (s, 3H), 6.82 (s, (pyridin-3-yl)-1,2,4- amine (0.19 g, 0.75 Mass 1H), 7.15-7.17 (m, triazin-3-amine (11 mmol) and 3-chloro- spectroscopy: 1H), 7.27 (s, 1H), mg, 5%) 5- (ESI +ve) 297.9.0 7.40 (m, 1H), 7.59 methylphenylboronic [M + H].sup.+, 295.9 (bs, 2H), 7.77 (m, acid (0.166 g, 0.98 [M + H].sup.− 1H), 8.56 (m, 1H), mmol) 8.61 (m, 1H). (ccxvii) 6-(3,5- 6-bromo-5- HPLC purity: (400 MHz, DMSO) δ: dichlorophenyl)-5- (pyrimidin-2-yl)-1,2,4- 97.14% (210 nm) 7.21 (s, 2H), 7.58 (s, (pyrimidin-2-yl)-1,2,4- triazin-3-amine (0.5 Mass 1H), 7.65 (t, 1H), 7.84 triazin-3-amine (40 g, 1.98 mmol) and spectroscopy: (bs, 2H), 8.93 (d, 2H). mg, 6%) 3,5- (ESI +ve) 318.9 dichlorophenylboronic [M + H].sup.+, 316.9 acid (0.414 g, 2.18 [M + H].sup.−. mmol) (ccxviii) 6-[3-chloro-5- 6-bromo-5- HPLC purity: (400 MHz, DMSO) δ: (trifluoromethyl)phe- (pyrimidin-2-yl)-1,2,4- 93.30% (202 nm) 7.38 (s, 1H), 7.64 (m, nyl]-5-(pyrimidin-2-yl)- triazin-3-amine (0.50 Mass 2H), 7.86 (m, 3H), 1,2,4-triazin-3-amine g, 1.98 mmol) and 3- spectroscopy: 8.91 (d, 2H). (0.130 g, 19%) chloro-5- (ESI +ve) 353.0 (trifluoromethyl) [M + H].sup.+, 351.0 phenylboronic acid [M + H].sup.−. (0.488 g, 2.18 mmol) (ccxix) 6-[2-bromo-6- 6-bromo-5-phenyl- HPLC purity: (400 MHz, DMSO) δ: (trifluoromethyl)pyridin- 1,2,4-triazin-3-amine 94.90% (272 nm) 7.47 (m, 5H), 7.74 (s, 4-yl]-5-phenyl- (0.25 g, 0.9 mmol) Mass 1H), 7.84 (s, 1H), 1,2,4-triazin-3-amine and 2-bromo-4- spectroscopy: 7.88 (bs, 2H). (30 mg, 8%) (4,4,5,5-tetramethyl- (ESI +ve) 396.1 1,3,2-dioxaborolan-2- [M + H].sup.+, 397.9 yl)-6- [M + H].sup.+. (trifluoromethyl)pyridine (0.52 g, 1.48 mmol) (ccxx) 6-[3-chloro-5- 6-bromo-5-(pyridin-3- HPLC purity: (400 MHz, DMSO) δ: (trifluoromethyl)phe- yl)-1,2,4-triazin-3- 91.22% (266 nm) 7.41 (m, 1H), 7.62 (s, nyl]-5-(pyridin-3-yl)- amine (0.20 g, 0.79 Mass 1H), 7.72 (bs, 2H), 1,2,4-triazin-3-amine mmol) and 3-chloro- spectroscopy: 7.76-7.80 (m, 2H), (8 mg, 3%) 5- (ESI +ve) 351.8 7.87 (s, 1H), 8.58 (m, (trifluoromethyl)phe- [M + H].sup.+, 349.9 1H), 8.62-8.64 (m, nylboronic acid (0.21 [M + H].sup.− 1H). g, 0.95 mmol) (ccxxi) 6-(3-chloro-5- 6-bromo-5- HPLC purity: (400 MHz, DMSO) δ: methylphenyl)-5- (pyrimidin-2-yl)-1,2,4- 95.27% (266 nm) 2.21 (3H, s), 6.98 (m, (pyrimidin-2-yl)-1,2,4- triazin-3-amine (0.5 Mass 2H), 7.21 (s, 1H), triazin-3-amine (130 g, 1.98 mmol) and 3- spectroscopy: 7.62 (t, 1H), 7.74 (s, mg, 22%) chloro-5- (ESI +ve) 299.0 2H), 8.90 (d, 2H) methylphenylboronic [M + H].sup.+, acid (0.650 g, 2.18 mmol)

[1314] The following compounds were prepared according to a modified version of the general procedure described for Example 1. In these cases, the reactions were run using using palladium acetate (1.5 mol %), dppf (3.0 mol %), copper bromide (1.5 eq.), caesium carbonate (2.0 eq.) and DMF (0.8 mL).

TABLE-US-00007 No. Product (yield) Prepared From LCMS NMR (ccxxii) 6-(6-chloropyridin- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 2-yl)-5-phenyl- 1,2,4-triazin-3-amine spectroscopy: m/z 7.31 − 7.39 (m, 4H), 1,2,4-triazin-3- (100 mg, 0.398 284.7 (M+H).sup.+ 7.39 − 7.46 (m, 1H), amine (7 mg, 6%) mmol), 6- (ES.sup.+), at 3.75 min, 7.47 (dd, J = 8.0, 0.8 chloropyridin-2- 99.2% purity Hz, 1H), 7.66 (s, 2H), ylboronic acid (141 (method B). 7.77 (dd, J = 7.6, 0.8 mg, (0.896 mmol) Hz, 1H), 7.95 (t, J = 7.8 Hz, 1H). (ccxxiii) 6-(4- 6-bromo-5-phenyl- Mass (400 MHz, CDCl.sub.3) δ: cyclopropylpyridin- 1,2,4-triazin-3-amine spectroscopy: m/z 0.89 − 1.01 (m, 4H), 2-yl)-5-phenyl- (50 mg, 0.199 mmol), 290.6 (M+H).sup.+ 1.97 − 2.06 (m, 1H), 1,2,4-,triazin-3- and 4-cyclopropyl-2- (ES.sup.+); 288.9 (M−H).sup.− 550 (s, 2H), 6.98 amine (3 mg, 5% (4,4,5,5-tetramethyl- (ES.sup.−), at 3.93 min (dd, J = 5.2, 1.7 Hz, 1,3,2-dioxaborolan-2- 99.4% purity 1H), 7.26 − 7.29 (m, yl)pyridine (110 mg, (method B). 1H), 7.33 − 7.41 (m, 0.448 mmol), 2H), 7.43 − 7.50 (m, 3H), 8.35 (d, J = 4.8 Hz, 1H). (ccxxiv) 5-phenyl-6-(6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethyl) 1,2,4-triazin-3-amine spectroscopy: m/z 7.27 − 7.35 (m, 4H), pyridin-2-yl)- (100 mg, 0.398 318.6 (M+H).sup.+ 7.36 − 7.44(m, 1H), 1,2,4-triazin-3- mmol), 2-(4,4,5,5- (ES.sup.+); 316.9 (M−H).sup.− 7.69 (s, 2H), 7.84 amine (27 mg, tetramethyl-1,3,2- (ES.sup.−), at 4.09 min, (dd, J 7.4, 1.3 Hz, 29%) dioxaborolan-2-yl)-6- 98.9% purity 1H), 8.11 − 8.23 (m, (trifluoromethyl) (method B). 2H). pyridine (245 mg, 0.896 mmol) (ccxxv) 5-pheryl-6-(4- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethyl) 1,2,4-triazin-3-amine spectroscopy: m/z 7.26 − 7.38 (m, 4H), pyridin-2-yl)-1,2,4- (100 mg, 0.398 318.7 (M+H).sup.+ 7.38 − 7.45 (m, 1H), triazin-3-amine mmol), 2-(4,4,5,5- (ES.sup.+); 316.9 (M−H).sup.− 7.69 (s, 2H), 7,74 (10 mg, 8%) tetramethyl-1,3,2- (ES.sup.−), at 4.12 min, (dd, J 5.1, 1.1 Hz, dioxaborolar-2-yl)-4- 98.5% purity 1H), 8.18 (s, 1H), (trifluoromethyl)pyridi (method B). 8.63 (d, J 5.1 Hz, ne (245 mg, 0.896 1H), mmol) (ccxxvi) 6-(6- 6-bromo-5-phenyl- Mass (400 MHz, CDCl.sub.3) δ: cyclopropylpyrdin- 1,2,4-triazin-3-amine spectroscopy: m/z 0.21 − 0.32 (m, 2H), 2-y)-5-phenyl- (50 mg, 0.199 mmol), 290.3 (M+H).sup.+ 0.55 − 0.64 (m, 2H), 1,2,4-triazin- 2-cyclopropyl-6- (ES.sup.+), at 1.85 min, 1.77 (dd, J8.1, 4.7 3-amine (4,4,5,5-tetramethyl- 98.4% purity Hz, 1H), 5.41 (s, 2H), (2 mg, 3%) 1,3,2-dioxaborolan-2- (method B). 7.11 (dd, J 7.7, 1,0 yl)pyridine (110 mg, Hz − 1H), 7.28 − 7.42 0.448 mmol) (m, 5H), 7.61 − 7.68 (m, 1H), 7.75 (dd, J 7.7, 1.0 Hz, 1H). (ccxxvii) 5-(3-amino-5- 6-bromo-5-phenyl- Mass (400 MHz, CDC1.sub.3) δ: phenyl-1,2,4- 1,2,4-triazin-3-amine spectroscopy: m/z 5.34 (s. 21-1), 7.42 − triazin-6-yl) (80 mg, 0.319 mmol), 267.2 (M+H).sup.+ 7.52 (m − 3H), 8.03 − pyrazin-2-ol 5-(4,4,5,5- (ES.sup.+), at 1.52 min, 8.09 (m, 3H), 8.31 (d, (2 mg, 2%) tetramethyl-1,3,2- 96.4% purity J 2.6 Hz, 1H), 8.57 dioxaborolan-2- (method B). (d, J7.5 Hz; 1H). yl)pyrazin-2-ol (159 mg, 0.717 mmol),

Alternative Procedure for the Preparation of 5,6-Biaryl-3-amino-1,2,4-triazines

[1315] The Suzuki reaction to form 5,6-biaryl-3-amino-1,2,4-triazines may alternatively be performed with palladium-containing catalysts such as dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II) or dichloro[1,1′-bis(di-tert-butylphosphino)]ferrocene palladium(II). Residual palladium species may then be removed from a solution of the triazine by treatment with a suitable scavenging agent, such as mercaptopropyl-funtionalised silica (Quadrasil-MP; available from Johnson Matthey) or macroporous polystyrene-bound 2,4,6-trimercaptotriazine (MP-TMT; available from Biotage).

Typical Alternative to the General Procedure, as Exotified with Example 1(xcv)

[1316] 6-bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (1 molar eq.), 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-methylpyridine (1 molar eq.) and K.sub.2CO.sub.3 (1.5 molar eq.) are suspended in a mixture of 1,4-dioxane and water (2:1; 10 mL of solvent per gram of bromotriazine). The resulting mixture is degassed, treated with dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (2 mol %) and refluxed until full consumption of bromotriazine is observed by LCMS. The cooled reaction mixture is then diluted with water, extracted with DCM and passed through a phase separator. The organic phase is concentrated under reduced pressure and purified by gradient flash chromatography, eluting with mixtures of ethyl acetate and hexanes to afford 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (61%).

Typical Alternative to General Procedure, as Exemplified with Example 1(ccix)

[1317] 6-bromo-5-phenyl-1,2,4-triazin-3-amine (1 molar eq.), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (1 molar eq.) and K.sub.2CO.sub.3 (1.5 molar eq.) are suspended in a mixture of 1,4-dioxane and water (2:1; 10 mL of solvent per gram of bromotriazine). The resulting mixture is degassed, treated with dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (2 mol %) and refluxed until full consumption of bromotriazine is observed by LCMS. The cooled reaction mixture is then diluted with water, extracted with DCM and passed through a phase separator. The organic phase is concentrated under reduced pressure and purified by gradient flash chromatography, eluting with mixtures of ethyl acetate and hexanes to afford 6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine (90%).

General Procedure for the Removal of Palladium Contaminants from 5,6-Biaryl-3-amino-1,2,4-triazines

[1318] A solution of a 5,6-biaryl-3-amino-1,2,4-triazine derivative (100 mg) in DCM (1.5 mL) is treated with Quadrasil-MP (42 mg) or MP-TMT (35 mg). The resulting mixture is heated to 50° C. for up to 24 hours then filtered. The filtrate is then concentrated under reduced pressure and the procedure repeated, if necessary.

[1319] Quadrasil-MP is available from Johnson Matthey, MP-TMT is available from Biotage.

Example 2

[1320] ##STR00040##

General Procedure for the Preparation of 5-Aryl-3,6-diamino-1,2,4-triazines

[1321] Intermediate D, a 6-halo-5-aryl-1,2,4-triazin-3-amine derivative (0.80 mmol) is dissolved in dioxane or N-methyl-2-pyrolidone (5 mL) and treated with an amine (1.60 mmol) and an aqueous solution of K.sub.2CO.sub.3 (0.22 g, 1.60 mmol in 0.5 mL water). The mixture is heated in a microwave for two hrs at 140° C. with TLC monitoring (hexane/ethyl acetate, 1:1). After completion of the reaction the mixture is poured into water (50 mL) and extracted with ethyl acetate (2×100 mL). The organic layers are combined, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude compound, product B, is purified by gradient flash chromatography or preparative HPLC.

(i) 5-Phenyl-6-(piperidin-1-yl)-1,2,4-triazin-3-amine

[1322] 5-Phenyl-6-(piperidin-1-yl)-1,2,4-triazin-3-amine (18 mg, 18%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and piperidine (0.14 g, 1.60 mmol) according to the general procedure of Example 2.

[1323] HPLC purity: 96.95% (264 nm)

[1324] Mass spectroscopy: (ESI +ve) 256.0 [M+H]

[1325] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 1.56-1.62 (m, 6H), 3.03 (m, 4H), 4.89 (s, 2H), 7.44-7.55 (m, 3H), 8.12 (m, 2H).

(ii) 6-(Morpholin-4-yl)-5-phenyl-1,2,4-triazin-3-amine

[1326] 6-(Morpholin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (50 mg, 20%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and morpholine (0.126 g, 1.44 mmol) according to the general procedure of Example 2.

[1327] HPLC purity: 94.87% (265 nm)

[1328] Mass spectroscopy: (ESI +ve) 257.9 [M+H].sup.+

[1329] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 2.88 (t, 4H), 3.59 (t, 4H), 6.75 (s, 2H), 7.54 (m, 3H), 8.06 (m, 2H).

(iii) 6-(3-Methylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine

[1330] 6-(3-Methylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (30 mg, 14%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and 3-methylpiperidine (0.21 g, 1.92 mmol) according to the general procedure of Example 2.

[1331] HPLC purity: 98.87% (215 nm)

[1332] Mass spectroscopy: (ESI +ve) 270.0 [M+H].sup.+

[1333] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 0.75 (d, 3H), 0.97 (m, 1H), 1.45 (m, 2H), 1.65 (m, 2H), 2.20 (m, 2H), 3.14 (m, 2H), 6.65 (s, 2H), 7.49 (m, 3H), 8.04 (m, 2H).

(iv) 6-(2,6-Dimethylmorpholin-4-yl)-5-phenyl-1,2,4-triazin-3-amine

[1334] 6-(2,6-Dimethylmorpholin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (35 mg, 10%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 2,6-dimethylmorpholine (0.27 g, 2.39 mmol) according to the general procedure of Example 2.

[1335] HPLC purity: 90% (271 nm)

[1336] Mass spectroscopy: (ESI +ve) 286.0 [M+H].sup.+

[1337] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 1.10 (s, 6H), 2.52 (t. 2H), 3.23 (d, 2H), 3.71 (m, 2H), 5.06 (b, 2H), 8.07 (m, 3H), 8.07 (d, 2H).

(v) 6-(4,4-Difluoropiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine

[1338] 6-(4,4-Difluoropiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (39 mg, 14%) was prepared from 6-chloro-5-phenyl-1,2,4-triazin-3-amine (0.20 g, 0.96 mmol), K.sub.2CO.sub.3 (0.23 g, 1.67 mmol) and 4,4-difluoropiperidine hydrochloride (0.22 g, 1.45 mmol) according to the general procedure of Example 2.

[1339] HPLC purity: 98.48% (262 nm)

[1340] Mass spectroscopy: (ESI +ve) 292.0 [M+H].sup.+

[1341] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 1.97 (m, 4H), 3.04 (m, 4H), 6.76 (s, 2H), 7.51 (m, 3H), 8.06 (m, 2H).

(vi) 6-(3,3-Dimethylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine

[1342] 6-(3,3-Dimethylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (54 mg, 10%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and 3,3-dimethylpiperidine (0.27 g, 2.39 mmol) according to the general procedure of Example 2.

[1343] HPLC purity: 88% (274 nm)

[1344] Mass spectroscopy: (ESI +ve) 284.1 [M+H].sup.+

[1345] .sup.1H NMR: (400 MHz, DMSO) δ: 0.89 (s, 6H), 1.24 (m, 2H), 1.40 (m, 2H), 2.65 (m, 2H), 2.70 (m, 2H), 6.67 (s, 2H), 7.49 (m, 3H), 7.94 (m, 2H).

(vii) 5-Phenyl-6-[3-(trifluoromethyl)piperidin-1-yl]-1,2,4-triazin-3-amine

[1346] 5-Phenyl-6-[3-(trifluoromethyl)piperidin-1-yl]-1,2,4-triazin-3-amine (50 mg, 8%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and 3-(trifluoromethyl)piperidine (0.40 g, 2.58 mmol) according to the general procedure of Example 2.

[1347] HPLC purity: 97.6% (263 nm)

[1348] Mass spectroscopy: (ESI +ve) 324.1 [M+H].sup.+

[1349] .sup.1H NMR: (400 MHz, DMSO) δ: 1.35 (m, 1H), 1.48 (m, 1H), 1.57 (m, 1H), 1.90 (m, 1H), 2.48 (m, 2H), 2.73 (m, 1H), 3.05 (m, 1H), 3.50 (m, 1H), 6.74 (s, 2H), 7.50 (s, 3H), 8.02 (m, 2H).

(viii) 6-(Octahydroquinolin-1(2H)-yl)-5-phenyl-1,2,4-triazin-3-amine

[1350] 6-(Octahydroquinolin-1(2H)-yl)-5-phenyl-1,2,4-triazin-3-amine (39 mg, 7%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (1.00 g, 3.96 mmol) and decahydroquinoline (0.60 g, 4.36 mmol) according to the general procedure of Example 2.

[1351] HPLC purity: 98.75% (282 nm)

[1352] Mass spectroscopy: (ESI +ve) 310.1 [M+H].sup.+

[1353] .sup.1H NMR: (400 MHz, DMSO) δ: 0.83 (m, 1H), 1.41 (m, 6H), 1.54 (m, 6H), 2.62 (m, 1H), 2.80 (m, 2H), 6.93 (bs. 2H), 7.47 (m, 3H), 8.15 (m, 2H).

(ix) 6-(3-Methoxypiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine

[1354] 6-(3-Methoxypiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (33 mg, 4%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.70 g, 2.78 mmol), K.sub.2CO.sub.3 (0.80 g, 5.85 mmol) and 3-methoxy piperidine HCl (0.52 g, 3.34 mmol) according to the general procedure of Example 2.

[1355] HPLC purity: 99.32% (266 nm)

[1356] Mass spectroscopy: (ESI +ve) 286.0 [M+H].sup.+

[1357] .sup.1H NMR: (400 MHz, DMSO) δ: 1.36 (m, 1H), 1.45 (m, 1H), 1.59 (m, 1H), 1.84 (m, 1H), 2.48 (m, 1H), 2.60 (m, 1H), 3.03 (m, 4H), 3.25 (m, 2H), 7.57 (m, 3H), 7.26 (bs, 2H), 7.99 (m, 2H).

(x) 6-(3-Ethynylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine

[1358] 6-(3-Ethynylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (10 mg, 2%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.60 g, 2.40 mmol) and 3-ethynyl piperidine HCl (0.42 g, 2.87 mmol) according to the general procedure of Example 2.

[1359] HPLC purity: 95.99% (266 nm)

[1360] Mass spectroscopy: (ESI +ve) 280.0 [M+H]+

[1361] .sup.1H NMR: (400 MHz, DMSO) δ: 1.08-1.80 (m, 5H), 2.64 (m, 2H), 2.86 (m, 2H), 3.23 (t. 1H), 6.7 (bs, 2H), 7.48 (m, 3H), 8.06 (d, 2H).

(xi) 6-(2,6-Dimethylmorpholin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine

[1362] 6-(2,6-Dimethylmorpholin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (110 mg, 20%) was prepared from 6-bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (0.50 g, 1.87 mmol) and 2,6-dimethylmorpholine (1.06 g, 9.36 mmol) according to the general procedure of Example 2.

[1363] HPLC purity: 93.61% (264 nm)

[1364] Mass spectroscopy: (ESI +ve) 304 [M+H]+

[1365] .sup.1H NMR: (400 MHz, DMSO) δ: 1.12 (d, 6H), 2.54 (m, 2H), 3.19 (d, 2H), 3.30 (m, 2H), 5.13 (bs, 2H), 7.16 (m, 2H), 8.16 (m, 2H).

[1366] The following compounds were prepared by reacting the indicated starting materials with potassium carbonate (83 mg, 0.60 mmol) in 1,4-dioxane (0.8 mL) and water (0.2 mL) at 140° C. for 18 hours, unless a shorter time is specified:

TABLE-US-00008 No. Product (yield) Prepared From LCMS NMR (xii) 6-(2- 6-bromo-5- Mass (400 MHz, DMSO) δ: ethylmorpholino)- phenyl-1,2,4- spectroscopy: 0.73 (t, J 7.5, 3H), 5-phenyl-1,2,4- triazin-3-amine m/z 286 (M+H).sup.+ 1.22 − 1.44 (m, 2H), triazin-3-amine (150 mg, 0.597 (ES.sup.+), at 4.03 2.38 − 2.47 (m, 1H), (60 mg, 35%) mmol). 2- min, 100% 2.65 − 2.77 (m, 1H), ethylmorpholine (method B). 3.02 (d, J 12.2, 1H), (344 mg, 3.12 (d, J 12.2, 1H), 2.99 mmol) 3.33 (s, 1H), 3.48 − 3.58 (m, 1H), 3.77 (d, J 11.1, 1H), 6.74 (s, 2H), 7.48 − 7.57 (m, 3H), 8.01 − 8.08 (m, 2H): (xiii) 5-phenyl-6-(6-oxa- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 9-azaspiro[4.5] 1,2,4-triazin-3-amine spectroscopy: 1.27 − 1.44 (m, 2H), decan-9-yl)-1,2,4- (150 mg, 0.597 m/z 312 (M+H).sup.+ 1.47 − 1.76 (m, 6H), triazin-3-amine mmol), 6-oxa-9- (ES.sup.+), at 4.24 2.71 − 2.81 (m, 2H), (48 mg, 25%) azaspiro[4.5]decane min, 97% purity 2.84 (s, 2H), 3.47 − hydrochloride (425 (method B). 3.63 (m, 2H), 6.77 (s, mg, 2.390 mmol) 2H), 7.48 − 7.57 (m, 3H), 7,94 − 8.01 (m, 2H), (xiv) 6-(2,2- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ; diethylmorpholino)- 1,2,4-triazin-3-amine spectroscopy; 0.67 (t, J 7.5, 6H), 5-phenyl-1,2,4- (150 mg, 0.597 m/z 314 (M+H).sup.+ 1.33 (dq, J 14.8, 7.5, triazin-3-amine mmol), 2.2- (ES.sup.+), at 4.64 2H), 1.65 (dq, j 14.9, (47 mg, 25%) diethylmorpholine min, 100% 7.5, 2H), 2.71 − 2.82 (428 mg, 2.99 mmol) (method B). (m, 4H), 3.47 − 3.58 (m, 2H), 6.78 (s, 2H), 7.45 − 7.57 (m, 3H), 7.85 − 7.95 (m, 2H). (xv) 6-(2,2- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: dimethylmorpholino)- 1,2,4-triazin-3-amine spectroscopy; 1.14 (s, 6H), 2.69 − 5-phenyl-1,2,4- 150 mg, 0.597 m/z 286 (M+H).sup.+ 2.77 (m, 2H), 2.79 (s, triazin-3-amine (41 mmol), 2.2- (ES.sup.+), at 4.03 2H), 3.49 − 3.62 (m, mg, 24%); prepared dimethylmorpholine min, 98% 2H), 6.77 (s, 2H), in 6 hours (344 mg, 2.99 mmol) (method B). 7.48 − 7.56 (m, 3H), 7.92 − 8.00 (m, 2H). (xvi) (1-(3-amino-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: phenyl-1,2,4-triazin- 1,2,4-triazin-3-amine spectroscopy: 0.88 (s, 3H), 1.10 − 6-yl)-3- (150 mg, 0.597 m/z 300 (M+H).sup.+ 1.20 (m, 1H), 1.31 − methylpiperidin-3- mmol), (3- (ES.sup.+), at 4.10 1.45 (m, 3H), 2.54 − yl)methanol (35 mg, methylpiperidin-3- min, 99% 2.63 (m, 1H), 2.63 − 19%); prepared in 6 yl)methanol (386 mg, (method B). 2.72 (m, 1H), 2.75 − hours 2.99 mmol) 2.93 (m, 2H), 3.23 (d, J 5,6, 2H), 4.51 (t, J 5.5, 1H), 6.68 (s, 2H), 7.47 − 1.55 (m, 3H), 7.92 − 8.00 (m, 2H). (xvii) 6-(3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (methoxymethyl) 1,2,4-triazin-3-amine spectroscopy: 0.95 − 1.12 (m, 1H), piperidin-1-yl)-5- (150 mg, 0.597 m/z 300 (M+H).sup.+ 1.37 − 1.60 (m, 2H), phenyl-1,2,4- mmol), cis-3- (ES.sup.+), at 4.4 1.61− 1.73 (m, 1H), triazin-3-amine (methoxymethyl)pipe min, 100% 1.80 − 1.94 (m, 1H), (75 mg, 42%) ridine (386 mg, 2.99 (method B). 2.37 − 2.47 (m, 1H), mmol) 2.50 − 2.58 (m, 1H), 3.03 − 3.21 (m, 6H), 3.28 − 3.34 (m, 1H), 6.68 (s, 2H), 7.47 − 7.56 (m, 3H), 7.99 − 8.09 (m, 2H), (xviii) 1-(1-(3-amino-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: phenyl-1,2,4-triazin- 1,2,4-triazin-3-amine spectroscopy: 0.91 − 1.03 (m, 1H), 6-yl)piperidin-3- (150 mg, 0.597 w/z m/z 300 1.22 − 1.32 (m, 2H), yl)ethanol (80 mg, mmol) and 1- (M+H).sup.+ (ES.sup.+), 1.38 − 1.59 (m, 2H), 43%) (piperidin-3- at 3.98 min, 96% 1.59 − 1.69 (m, 1H), yl)ethanol (77 mg, (method B). 1.69 − 1.80 (m, 1H), 0.597 mmol) 2.28 − 2.38 (m, 1H), 2.47 − 2.56 (m, 1H), 3.07 − 3.16 (m, 1H), 3.18 − 3.30 (m, 3H), 4.25 − 4.38 (m, 1H), 6.68 (s, 2H), 7.46 − 7.57 (m, 3H), 7.99 − 8.09 (m, 2H). (xix) (1-(3-amino-5- piperidin-3- Mass (400 MHz, DMSO) δ; phenyl-1,2,4-triazin- ylmethanol (344 mg, spectroscopy; m/z 0.94 − 1.08 (m, 1H), 6-yl)piperidin-3- 2.99 mmol) 6-bromo- 286 (M+H).sup.+ (ES.sup.+), 1.34 − 1.57 (m, 2H), yl)methanol (18 mg, 5-phenyl-1,2,4- at 3.78 min, 94% 1.61 − 1.74 (m, 2H), 10%) triazin-3-amine (150 (method B). 2.38 − 2.61 (m, 2H), mg, 0.597 mmol) 3.04 (s, 1H), 3.13 − 3.46 (m, 3H), 4.44 (t, J = 5.3 Hz, 1H), 6.67 (s, 2H), 7.45 − 7.57 (m, 3H), 7.98 − 8.11 (m, 2H). (xx) 1-(1-(3-amino-5- 1-(piperidin-3- Mass (400 MHz, DMSO) δ: phenyl-1,2,4-triazin- yl)ethanone (380 mg, spectroscopy: m/z 1.30 − 1.51 (m, 2H), 6-yl)piperidin-3- 2.99 mmol), 6- 298 (M+H).sup.+ (ES.sup.+): 1.52 − 1.63 (m, 1H), yl)ethanone (13 mg, bromo-5-phenyl- at 3.92 min, 1.85 − 1.96 (m, 1H), 7%) 1,2,4-triazin-3-amine 95.06% (method 2.01 (s, 3H), 2.62 − (150 mg, 0.597 B). 2.71 (m, 1H), 2.71 − mmol) 2.83 (m, 1H), 2.95 − 3.12 (m, 1H), 3.31 − 3.46 (m, 2H), 6.72 (s, 2H), 7.46 − 7.56 (m, 3H), 7.97 − 8.08 (m, 3H). (xxi) 6- 6-bromo-5-phenyl- HPLC purity: (400 MHz, DMSO) δ: (octahydroisoquinolin- 1,2,4-triazin-3-amine 97.40 % (277 nm); 0.85 (m, 3H), 1.14 2(1H)-yl)-5-phenyl- (2.00 g, 7.96 mmol) mass (m, 4H), 1.36 (m, 2H), 1,2,4-triazin-3-amine and per spectroscopy; 1.54 (m, 3H), 2.26 (54.2 mg, 2.1 %); hydroisoquinoline (ESI +ve) m/z (m, 1H), 2.51 (m, 1H), prepared in 8 hours (2.21 g, 15.9 mmol) 310.1 [M+H].sup.+ 3.10 (m, 2H), 6.61 (bs, 2H), 7,48 (m, 3H), 8.04 (dd, 2H). (xxii) N.sup.6-(4-methyl-1,3- 6-bromo-5-phenyl- HPLC purity: (400 MHz, DMSO) δ; thiazol-2-yl)-5- 1,2,4-triazin-3-amine 99.03% (298 nm); 2.10 (5, 3H), 6.18 (s, phenyl-1,2,4-triazine- (1.00 g, 3.98 mmol) mass 1H), 6.53 (bs, 2H), 3,6-diamine (10 mg, and 2-amino-4- spectroscopy: 7.48 (m, 3H), 8.15 1%) methyl thiazole (1.36 (ESI +ve) m/z (m, 2H), 11.61 (b, g, 11.95 mmol) 284.9 [M+H].sup.+ 1H). (xxiii) 5-phenyl-6-[4- 6-bromo-5-phenyl- HPLC purity: (400 MHz, DMSO) δ: (trifluoromethyl) 1,2,4-triazin-3-amine 99.9% (218 nm); 1.46 (m, 2H), 1.75 piperidin-1-yl]- (1.0 g, 3.9 mmol) and mass (m, 2H), 2.34 (m, 1H) 1,2,4-triazin-3- 4-trifluoromethyl spectroscopy: 2.66 (m, 2H), 3.23 amine (20 mg, 2%) piperidine (ESI +ve) m/z (m, 2H), 6.72 (s, 2H), hydrochloride (0.9 g, 323.9 [M].sup.+ 7.51 (m, 3H), 8.02 4.8 mmol) (m, 2H). (xxiv) 5-phenyl-6-(3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: phenylpiperidin-1-yl)- 1,2,4-triazin-3-amine spectroscopy: m/z 1.51 − 1.77 (m, 3H), 1,2,4-triazin-3-amine (150 mg, 0.597 332 (M+H).sup.+ (ES.sup.+), 1.83 − 1.92 (m, 1H), (62 mg, 31%) mmol), 3- at 4.92 min, 100% 2.58 − 2.72 (m, 2H), phenylpiperidine (method B). 2.74 − 2.84 (m, 1H), (482 mg, 2.99 mmol) 3.24 (d, J 11.7, 1H) 3.34 (d: J 11.7, 1H), 6.67 (s, 2H), 7.04 − 7.12 (m, 2H), 7.13 − 7.20 (m, 1H), 7.20 − 7.28 (m, 2H), 7.52 − 7.58 (m, 3H), 8.03 − 8.13 (m, 2H). (xxv) (4-(3-amino-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: phenyl-1,2,4-triazin- 1,2,4-triazin-3-amine spectroscopy: 2.51 − 2.58 (m, 1H), 6-yl)morpholin-2- (150 mg, 0.597 m/z 288 (M+H).sup.+ 2.63 − 2.74 (m, 1H), yl)methanol (40 mg, mmol), morpholin-2- (ES.sup.+), at 2.95 min, 2.91 − 3.02 (m, 1H), 23%) ylmethanol (350 mg, 100% (method B). 3.33 (s, 3H), 3.47 − 2.99 mmol) 3.58 (m, 2H), 3.70 − 3.79 (m, 1H), 4,67 (t, J 5.8, 1H), 6.76 (s, 2H), 7,47 − 7.56 (m, 3H), 8,03 − 8.11 (m, 2H), (xxvi) 5-phenyl-6-(3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (propoxymethyl)pyrro 1,2,4-triazin-3-amine spectroscopy: 0.80 (t, J 7.4, 3H), lidin-1-yl)-1,2,4- (150 mg, 0.597 m/z 314 (M+H).sup.+ 1.37− 1.58 (m, 3H), triazin-3-amine (39 mmol), 3- (ES.sup.+), at 1.81 − 1.94 (m, 1H), mg, 20%) (propoxymethyl)pyrro 4.64 min, 95% 2.29 − 2.40 (m, 2H), lidine (428 mg, 2.99 (method B). 2.85 (dd, j 10.3, 6.4, mmol) 1H), 3.00 − 3.13 (m, 3H), 3.18 − 3.30 (m, 3H), 6.38 (s, 2H), 7.45 − 7.53 (m, 3H), 7.69 − 7.79 (m, 2H). (xxvii) 2-(1-(3-amino-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: phenyl-1,2,4-triazin- 1,2,4-triazin-3-amine spectroscopy: 0.86 (s, 6H), 1.00 − 6-yl)piperidin-3- (150 mg, 0.597 m/z 314 (M+H).sup.+ 1.13 (m, 1H), 1.38 − yl)propan-2-ol (56 mmol), 2-(piperidin- (ES.sup.+), 4.22 1.52 (m, 2H), 1.58 − mg, 31%) 3-yl)propan-2-ol (257 min, 100% 1.69 (m, 1H), 1.78 − mg, 1.792 mmol) (method B). 1.88 (m, 1H), 2.30 (app t, J 11.6, 1H), 2.42 − 2.50 (m, 1H), 3.20 − 3.28 (m, 1H), 3.31 − 3.38 (m, 1H), 4.07 (s, 1H), 6.65 (s, 2H), 7.45 − 7.56 (m, 3H), 7.97 − 8.09 (m, 2H). (xxviii) 6- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (hexahydropyrrolo[1, 1,2,4-triazin-3-amine spectroscopy; 1.21 − 1.35 (m, 2H), 2-a]pyrazin- (150 mg, 0.597 m/z 297 (M+H).sup.+ 1.55 − 1.73 (m, 2H), 2(1H)-yl)-5- mmol), (ES.sup.+), at 1.96 − 2.20 (m, 3H), phenyl-1,2,4- octahydropyrrolo[1,2- 4.17 min, 100% 2.69 − 2.81 (m, 1H), triazin-3-amine a]pyrazine (377 mg, (method B). 2.81 − 3.03 (m, 2H), (16 mg, 9%) 2.99 mmol) 3.06 − 3.19 (m, 1H), 3.29 − 3.36 (m, 2H), 6.71 (s, 2H), 7.46 − 7.56 (m, 3H), 8.00 − 8.09 (m, 2H). (xxix) 1-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ; 1,2,4-triazin-6-yl)-3- 1,2,4-triazin-3-amine spectroscopy: 0.79 (t, J 7.4, 3H), ethylpiperidin-3-ol (150 mg, 0.597 m/z 300 (M+H).sup.+ 1.23 (s, 1H), 1.32 − (42 mg, 23%) mmol), 3- (ES.sup.+), at 4.14 1.52 (m, 4H), 1.54 − ethylpiperidin-3-ol min, 97% 1.68 (m, 1H), 2.59 − (386 mg, 2.99 mmol) (method B). 2.69 (m, 1H), 2.69 − 2.80 (m, 1H), 2.86 − 2.98 (m, 2H), 4.21 (s, 1H), 6.73 (s, 2H), 7.46 − 1.55 (m, 3H), 8.01 − 8.10 (m, 2H). (xxx) 2-(4-(3-amino-5- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: phenyl-1,2,4-triazin- 1,2,4-triazin-3-amine spectroscopy: 1.34 − 1.61 (m, 2H), 6-yl)morpholin-2- (150 mg, 0.597 m/z 302 (M+H).sup.+ 2.48 − 2.58 (m, 1H), yl)ethanol (42 mg, mmol), 2-morphonlin- (ES.sup.+), at 3.22 min, 2.62 − 2.74 (m, 1H), 22%); prepared in 3 2-yl)ethanol (392 mg, 96% (method B). 2.91 − 3.02 (m, 1H), hours 2.99 mmol) 3.09 − 3.20 (m, 1H), 3.27 − 3.42 (m, 2H), 3.46 − 3.56 (m, 1H), 3.56 − 3.67 (m, 1H), 3.68 − 3.78 (m, 1H), 4.39 (t, J 5.1, 1H), 6.74 (s, 2H), 7.47 − 7.58 (m, 3H), 7.99 − 8.12 (m, 2H).

Example 3

[1367] ##STR00041##

General Procedure for the Preparation of 3-amino-5-aryl-6-aryloxy-1,2,4-triazines

[1368] A solution of intermediate D, a 6-halo-5-aryl-1,2,4-triazin-3-amine, (1.99 mmol) in DMSO (5 mL) is treated sequentially with a phenol derivative (7.90 mmol), NaOH (0.31 g, 7.9 mmol) and cesium carbonate (0.64 g, 1.99 mmol). The resulting mixture is stirred at 90° C. overnight with TLC monitoring (hexane/ethyl acetate, 7:3). Upon completion of the reaction, the mixture is diluted with water (15 mL) and extracted with ethyl acetate (3×15 mL). The combined organic extracts are dried over sodium sulfate and concentrated in vacuo. The crude product, product C, is purified by gradient flash chromatography, eluting with mixtures of ethyl acetate in hexane (e.g. 15%) or by preparative HPLC.

(i) 6-Phenoxy-5-phenyl-1,2,4-triazin-3-amine

[1369] 6-Phenoxy-5-phenyl-1,2,4-triazin-3-amine (78 mg, 14%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.5 g, 1.99 mmol) and phenol (0.74 g, 7.90 mmol) according to the general procedure of Example 3.

[1370] HPLC purity: 99.67% (210 nm)

[1371] Mass spectroscopy: (ESI +ve) 265.0 [M+H].sup.+.

[1372] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 7.08 (s, 2H), 7.13 (m, 3H), 7.36 (m, 2H), 7.52 (m, 3H), 8.07 (m, 2H).

(ii) 6-(3-Aminophenoxy)-5-phenyl-1,2,4-triazin-3-amine

[1373] 6-(3-Aminophenoxy)-5-phenyl-1,2,4-triazin-3-amine (25 mg, 8%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3-amino phenol (0.19 g, 1.78 mmol) according to the general procedure of Example 3.

[1374] HPLC purity: 89.7% (238 nm)

[1375] Mass spectroscopy: (ESI +ve) 338.0 [M+H].sup.+

[1376] .sup.1H NMR: (400 MHz, DMSO) δ: 5.19 (s, 2H), 6.15 (m, 2H), 6.27 (m, 1H), 6.93 (m, 1H), 7.10 (s, 2H), 7.48-7.56 (m, 3H), 8.04 (d, 2H).

(iii) 6-(3-Fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine

[1377] 6-(3-Fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (78 mg, 23%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3-fluoro phenol (0.27 g, 2.39 mmol) according to the general procedure of Example 3.

[1378] HPLC purity: 99.67% (244 nm)

[1379] Mass spectroscopy: (ESI +ve) 283.1 [M+H].sup.+

[1380] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 5.29 (s, 2H), 6.87-6.95 (m, 3H), 7.33 (m, 1H), 7.48-7.58 (m, 3H), 8.23 (m, 2H).

(iv) 5-Phenyl-6-[2-(propan-2-yl)phenoxy]-1,2,4-triazin-3-amine

[1381] 5-Phenyl-6-[2-(propan-2-yl)phenoxy]-1,2,4-triazin-3-amine (20 mg, 7%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol) and 2-isopropyl phenol (0.43 g, 3.18 mmol) according to the general procedure of Example 3.

[1382] HPLC purity: 96.5% (245 nm)

[1383] Mass spectroscopy: (ESI +ve) 307.1 [M+H].sup.+

[1384] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 1.25 (d, 6H), 3.16 (m, 1H), 5.19 (s, 2H), 7.00 (m, 1H), 7.20 (m, 2H), 7.36 (m, 1H), 7.38-7.59 (m, 3H), 8.31 (m, 2H).

(v) 5-Phenyl-6-[3-(trifluoromethyl)phenoxy]-1,2,4-triazin-3-amine

[1385] 5-Phenyl-6-[3-(trifluoromethyl)phenoxy]-1,2,4-triazin-3-amine (21 mg, 4%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol) and 3-(trifluoromethyl)phenol (0.52 g, 3.18 mmol) according to the general procedure of Example 3.

[1386] HPLC purity: 88.72% (245 nm)

[1387] Mass spectroscopy: (ESI +ve) 332.9 [M+H].sup.+

[1388] .sup.1H NMR: (400 MHz, de-DMSO) δ: 7.10 (s, 2H), 7.49-7.63 (m, 5H), 7.61-7.63 (m, 2H), 8.07-8.09 (d, 2H).

(vi) 6-(4-Fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine

[1389] 6-(4-Fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (35 mg, 8%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol) and 4-fluorophenol (0.36 g, 3.18 mmol) according to the general procedure of Example 3.

[1390] HPLC purity: 96.39% (244 nm)

[1391] Mass spectroscopy: (ESI +ve) 283.1 [M+H].sup.+

[1392] .sup.1H NMR: (400 MHz, de-DMSO) δ: 7.03 (s, 2H), 7.20-7.22 (m, 4H), 7.50-7.56 (m, 3H), 8.08 (dd, 2H).

(vii) 6-(2-Fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine

[1393] 6-(2-Fluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (44 mg, 10%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol) and 2-fluorophenol (0.36 g, 3.18 mmol) according to the general procedure of Example 3.

[1394] HPLC purity: 90.06% (244 nm)

[1395] Mass spectroscopy: (ESI +ve) 283.1 [M+H].sup.+

[1396] .sup.1H NMR: (400 MHz, DMSO) δ: 7.04 (s, 2H), 7.25 (m, 2H), 7.37 (m, 2H), 7.53-8.11 (m, 3H), 8.12 (m, 2H).

(viii) 6-(4-Methoxyphenoxy)-5-phenyl-1,2,4-triazin-3-amine

[1397] 6-(4-Methoxyphenoxy)-5-phenyl-1,2,4-triazin-3-amine (45 mg, 13%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 4-methoxyphenol (0.30 g. 2.39 mmol) according to the general procedure of Example 3.

[1398] HPLC purity: 92.08% (218 nm)

[1399] Mass spectroscopy: (ESI +ve) 295.1 [M+H].sup.+

[1400] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 3.81 (s, 3H), 5.29 (s, 2H), 6.92 (d, 2H), 7.08 (d, 2H), 7.50-7.59 (m, 3H), 8.29 (m, 2H).

(ix) 6-[4-Fluoro-3-(trifluoromethyl)phenoxy]-5-phenyl-1,2,4-triazin-3-amine

[1401] 6-[4-Fluoro-3-(trifluoromethyl)phenoxy]-5-phenyl-1,2,4-triazin-3-amine (198 mg, 36%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol) and 4-fluoro-3-(trifluoromethyl)phenol (0.57 g, 3.18 mmol) according to the general procedure of Example 3.

[1402] HPLC purity: 95% (235 nm)

[1403] Mass spectroscopy: (ESI +ve) 350.9 [M+H].sup.+, (ESI −ve) 349.1 [M−H].sup.−.

[1404] .sup.1H NMR: (400 MHz, DMSO) δ: 7.05 (s, 2H), 7.50-7.62 (m, 5H), 7.75 (m, 1H), 8.10 (m, 2H).

(x) 5-Phenyl-6-[3-(trifluoromethoxy)phenoxy]-1,2,4-triazin-3-amine

[1405] 5-Phenyl-6-[3-(trifluoromethoxy)phenoxy]-1,2,4-triazin-3-amine (22 mg, 3%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and 3-(trifluoromethoxy)phenol (0.42 g, 2.39 mmol) according to the general procedure of Example 3.

[1406] HPLC purity: 95.6% (235 nm)

[1407] Mass spectroscopy: (ESI +ve) 348.9 [M+H].sup.+.

[1408] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 5.17 (s, 2H), 7.08 (m, 3H), 7.39 (t, 1H) 7.54 (m, 3H), 8.21 (d, 2H).

(xi) 6-(3-Chlorophenoxy)-5-phenyl-1,2,4-triazin-3-amine

[1409] 6-(3-Chlorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (147 mg, 31%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.58 mmol) 3-chloro phenol (0.40 g, 3.16 mmol) and K.sub.2CO.sub.3 (432 mg, 3.15 mmol), according to the general procedure of Example 3.

[1410] HPLC purity: 98% (245 nm)

[1411] Mass spectroscopy: (ESI +ve) 298.9 [M+H].sup.+

[1412] .sup.1H NMR: (400 MHz, DMSO) δ: 7.12 (s, 2H), 7.14 (m, 1H), 7.21 (m, 1H), 7.35 (m, 1H), 7.40 (m, 1H), 7.55 (m, 3H), 8.06 (m, 2H).

(xii) 6-(3,5-Dichlorophenoxy)-5-phenyl-1,2,4-triazin-3-amine

[1413] 6-(3,5-Dichlorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (89 mg, 17%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.40 g, 1.59 mmol) and 3-5-dichlorophenol (0.52 g, 3.18 mmol) according to the general procedure of Example 3.

[1414] HPLC purity: 99.03% (246 nm)

[1415] Mass spectroscopy: (ESI +ve) 332.9 [M+H]+

[1416] .sup.1H NMR: (400 MHz, DMSO) δ: 7.15 (s, 2H), 7.40 (m, 3H), 7.54 (m, 31-), 8.02 (d, 2H).

(xiii) 6-(3,5-Difluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine

[1417] 6-(3,5-Difluorophenoxy)-5-phenyl-1,2,4-triazin-3-amine (101 mg, 17%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and 3,5-difluorophenol (0.31 g, 3.98 mmol) according to the general procedure of Example 3.

[1418] HPLC purity: 90.33% (244 nm)

[1419] Mass spectroscopy: (ESI +ve) 300.9 [M+H].sup.+

[1420] .sup.1H NMR: (400 MHz, CDCl.sub.3) δ: 5.46 (bs, 2H), 6.65 (m, 1H), 6.71 (m, 2H), 7.50 (m, 2H), 7.58 (m, 1H), 8.12 (m, 2H).

[1421] The following compounds were prepared by reacting the indicated starting materials according to the general procedure of Example 3.

TABLE-US-00009 No. Product (yield) Prepared From LCMS NMR (xiv) 6-(3,5- 6-bromo-5- HPLC purity: (400 MHz, dimethylphenoxy)- phenyl-1,2,4- 96.6% (246 DMSO) δ: 5-phenyl-1,2,4- triazin-3-amine nm); mass 2.22 (s, 6H), triazin-3-amine (0.40 g, 1.59 spectroscopy: 6.71 (s, 2H), (26 mg, 5%) mmol) and (ESI +ve) m/z 6.76 (s, 1H) 3.5-(dimethyl) 293.0 [M+H].sup.+ 7.06 (s, 2H), phenol (0.39 g, 7.52 (m, 3H), 2.07 mmol) 8.05 (d, 2H). (xv) 6-(3-chloro-5- 6-bromo-5- HPLC purity: (400 MHz, methoxyphenoxy)- phenyl-1,2,4- 98% (245 DMSO) δ: 5-phenyl-1,2,4- triazin-3- nm); mass 3,74 (s, 3H), triazin-3-amine amine (0.40 g, spectroscopy: 6.75 (m, 1H), (120 mg, 23%) 1.59 mmol) and (ESI +ve) m/z 6.82 (m, 1H), 3-chloro-5- 328.9 [M+H].sup.+ 6.85 (m, 1H), methoxyphenol 7.12 (s, 2H), (0.50 g, 7.53 (m, 3H), 31.8 mmol) 8.03 (m, 2H).

[1422] The following compounds were prepared by heating the neat mixture of a phenol derivative and bromotriazine derivative (as indicated) with DBU (270 μl, 1.792 mmol), at 110° C. overnight:

TABLE-US-00010 No. Product (yield) Prepared From LCMS NMR (xvi) 1-(3-amino-5-phenyl- 6-chloro-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6- 1,2,4-triazin-3-amine spectroscopy: m/z 6.08 − 6.16 (m, 2H), yl)pyridin-4(1H)-one (0.082 g, 0.398 266,2 (M+H).sup.+ (ES.sup.+); 7.42 − 7.55 (m, 5H), (29 mg, 0.109 mmol, mmol), DBU (0.298 264.4 (M−H).sup.− (ES.sup.−), 7.68 − 7.77 (m, 4H). 27.5%) μl, 1990. mmol) and at 2.45 min, 100% pyridin-4-ol (189 mg, (method B) 1.990 mmol) (xvii) 6-(4-methylphenoxy)- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 5-phenyl-1,2,4- 1,2,4-triazin-3-amine spectroscopy: m/z 2.23 (s, 3H), 7.00 − triazin-3-amine (51 (90 mg, 0.358 279.82 (M+H).sup.+ 7.04 (m, 2H), 7.05 (s, mg, 51%) mmol), p-cresol (194 (ES.sup.+), at 4.75 min, 2H), 7.12 − 7.22 (m, mg, 1.792 mmol), 99 % (method B), 2H), 7,49 − 7.60 (m, and DBU (270 μl, 3H), 8.04 − 8.13 (m., 1.792 mmol) 2H), (xviii) 6-(4-chlorophenoxy)- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 5-phenyl-1,2,4- 1,2,4-triazin-3-amine spectroscopy: m/z 7.12 (s, 2H), 7.18 − triazin-3-amine. (38 (90 mg, 0.358 299.6 (M+H).sup.+ (ES.sup.+), 7.25 (m, 2H), 7.40 − mg, 35%) mmol), 4- at 4.77 min, 99% 7.46 (m, 2H), 7.49 − chlorophenol (230 (method B). 7.60 (m, 3H), 8.03 − mg, 1.792 mmol), 8.11 (m, 2H). and DBU (270 μl, 1.792 mmol) (xix) 6-(3,4- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: difluorophenoxy)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 7.03 − 7.11 (m, 1H), phenyl-1,2,4-triazin- (90 mg, 0.358 301.64 (M+H).sup.+ 7.11 (s, 2H), 7.41 − 3-amine mmol), 3.4- (ES.sup.+), 299.94 (M− 7.51 (m, 3H), 7.51 − difluorophenol (233 H).sup.− (ES.sup.−), at 4.59 7.61 (m, 3H), 8.03 − mg, 1.792 mmol), min, 97% (method 8.11 (m, 2H). and DBU (270 μl, B). 1.792 mmol) (xx) 6-[(6-methoxypyridin- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 3-yl)oxy]-5-phenyl- 1,2,4-triazin-3-amine spectroscopy: m/z 3.85 (s, 3H, 6.88 1,2,4-triazin-3-amine (90 mg, 0.358 296.0 (M+H).sup.+ (ES.sup.+); (dd, J 8.9, 0.5, 1H), mmol), 6- 4.59 min, 95% 7.00 (s, 2H), 7.52 − methoxypyridin-3-ol (method B). 7.63 (m, 3H), 7.68 (224 mg, 1.792 (dd, J 8.9, 3.0, 1H), mmol), and DBU 8.11 (dd, J 2.0, 0.5, (270 μl, 1.792 mmol) 1H), 8.12 − 8.16 (m, 2H). (xxi) 6-[(2-methylpyridin-3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: yl)oxy]-5-phenyl- 1,2,4-triazin-3-amine spectroscopy: m/z 2.38 (s, 3H), 7.95 (s, 1,2,4-triazin-3-amine (90 mg, 0.358 280.73 (M+H).sup.+ 2H), 7.28 (ddd, J 8.2, mmol), 2- (ES.sup.+), 278.94 (M− 4.7, 0.5, 1H), 7.52 − methylpyridin-3-ol H).sup.− (ES.sup.−), at 3.90 7.63 (m, 4H), 8.11 − (196 mg, 1.792 min, 99% (method 8.18 (m, 2H), 8.31 mmol), and DBU B). (dd, J 4.7, 1.4, 1H). (270 μl, 1.792 mmol) (xxii) 6-[(6-chloropyridin-3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: yl)oxy]-5-phenyl- 1,2,4-triazin-3-amine spectroscopy: m/z 7.14 (s, 2H), 7.51 − 1,2,4-triazin-3-amine (90 mg, 0.358 300.70 (M+H).sup.+ 7.63 (m, 4H), 7.83 mmol), 6- (ES.sup.+), at 3.90 min, (dd, J 8.7, 3.0, 1H), chloropyridin-3-ol 97% (method B). 8.06 − 8.13 (m, 2H), (232 mg, 1.792 8.42 (dd, J 3.0, 0.5, mmol), and DBU 1H), (270 μl, 1.792 mmol) (xxiii) 4-[(3-amino- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 5-phenyl-1,2,4- 1,2,4-triazin-3-amine spectroscopy: m/z 7.28 (s, 2H), 7.34 − triazin-6- (90 mg, 0.358 290.72 (M+H).sup.+ 7.39 (m, 2H), 7.48 − yl)oxy]benzonitrile mmol), 4- (ES+); 288.96 (M − 7.59 (m, 3H), 7.82 − hydroxybenzonitrile H).sup.− (ES.sup.−), at 4.09 7.90 (m, 2H), 8.00 − (213 mg, 1.792 min, 99% (method 8.05 (m, 2H). mmol), and DBU B). (270 μl, 1.792 mmol) (xxiv) 6-{[1-methyl-3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: (trifluoromethyl)-1H- 1,2,4-triazin-3-amine spectroscopy: m/z 3.79 (s, 3H), 6.58 (s, pyrazol-5-yl]oxy}-5- (90 mg, 0.358 337.60 (M+H).sup.+ 1H), 7.27 (s, 2H), phenyl-1,2,4-triazin- mmol), 1-methyl-3- (ES.sup.+); 335.81 (M− 7.52 − 7.66 (m, 3H), 3-amine (trifluoromethyl)-1H- H).sup.− (ES.sup.−), at 4.35 8.04 − 8.12 (m, 2H). pyrazol-5-ol (298 min, 97% (method mg, 1.792 mmol), B). and DBU (270 μl, 1.792 mmol) (xxv) 6-[(1-methyl-1H- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: benzimidazol-5- 1,2,4-triazin-3-amine spectroscopy: m/z 3.85 (s, 3H), 7.01 (s, yl)oxy]-5-phenyl- (90 mg, 0.358 319.69 (M+H).sup.+ 2H), 7.14 (dd, J 8.7, 1,2,4-triazin-3-amine mmol), 1-methyl-1H- (ES.sup.+), at 4.05 min, 2.2, 1H), 7.42 (d, J benzo[d]imidazol-5- 99% (method B), 2.1, 1H), 7.51 − 7.63 ol (266 mg, 1.792 (m, 4H), 8.12 − 8.19 mmol) and DBU (270 (m, 2H), 8.26 (s, 1H). μl, 1.792 mmol) (xxvi) 1-(3-amino-5-phenyl 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6- 1,2,4-triazin-3-amine spectroscopy: m/z: 6.54 (dd, J 8.0, 3.1, yl)pyridazin-4(1H)- (90 mg, 0.358 267.80.sup.+ (ES.sup.+); 1H), 7.41 − 7.56 (m, one mmol), pyridazin-4-ol 266.01 (M−H).sup.− (ES.sup.−), 5H), 7.74 (dd, J 3.1, (172 mg, 1.792 at 2.80 min, 96% 0.6, 1H), 7.90 (s, 2H), mmol), and DBU (method B). 8.60 (dd, J 8.0, 0.6, (270 μl, 1.792 mmol) 1H) (xxvii) 1-(3-amino-5-phenyl- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 1,2,4-triazin-6-yl)- 1,2,4-triazin-3-amine spectroscopy: m/z 7.44 − 7.60 (m, 5H), 3,5-diehloropyridin- (150 mg, 0.597 334.55 (M+H).sup.+ 7.94 (a, 2H), 8.42 (s, 4(1H)-one (10 mg, mmol), 3.5- (ES.sup.+), at 3.05 min, 2H). 5%) dichloropyridin-4-ol 96% (method B). (490 mg, 2.99 mmol), (xxviii) 6-(2,4- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: dichlorophenoxy)-5- 1,2,4-triazin-3-amine spectroscopy: 7.10 (s, 2H), 7.42 − phenyl-1,2,4-triazin- (90 mg, 0.358 m/z 333.5 (M+H)+ 7.51 (m, 2H), 7.54 − 3-amine (16 mg, mmol), 2.4- (ES+) at 5.03 min, 7.64 (m, 3H), 7.80 13%) dichlorophenol (292 98% purity (method J 2.4, 1H), 8.11 − mg, 1.792 mmol), B). 8.18 (m, 2H). and DBU (270 μl, 1.792 mmol) (xxix) 6-(2,4- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: difluorophenoxy)-5- 1,2,4-triazin-3-amine spectroscopy: m/z 7.06 (3, 2H), 7.12 − phenyl-1,2,4-triazin- (90 mg, 0.358 301.67 (M+H).sup.+ 7.21 (m, 1H), 7.44 − 3-amine (12 mg, mmol), 2.4- (ES.sup.+), 99% (method 7.65 (m, 5H), 8.09 − 11%) difluorophenol (233 B). 8.18 (m, 2H). mg, 1.792 mmol) and DBU (270 μl, 1.792 mmol) (xxx) 5-phenyl-6-(pyridin- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: 3-yloxy)-1,2,4-triazin- 1,2,4-triazin-3-amine spectroscopy: m/z 7.11 (s, 2H), 7.45 3-amine (90 mg, 0.358 266.76 (M+H).sup.+ (ddd, J 8.4, 4.7, 0.6, mmol), pyridin-3-ol (ES.sup.+); 264.96 (M+ 1H), 7.50 − 7.63 (m, (170 mg, 1.792 H).sup.− (ES.sup.−), at 3.70 3H), 7.69 (ddd, J 8.4, mmol) min, 99% (method 2.8, 1.4, 1H), 8.05 − B). 8.15 (m, 2H), 8.41 (dd, J 4.7, 1.3, 1H), 8.53 (d, J 2.5, 1H) (xxxi) 6-[(4-methylpyrid-3- 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: yl)oxy]-5-phenyl- 1,2,4-triazin-3-amine spectroscopy: m/z: 2.19 (s, 3H), 7.02 (s, 1,2,4-triazin-3-amine (90 mg, 0.358 280.79 (M+H).sup.+ 2H), 7.39 (d, J 4.9, mmol), 4- (ES.sup.+), at 3.97 min, 1H), 7.54 − 7.64 (m, methylpyridin-3-ol 99% (method B). 3H), 8.13 − 8.21 (m, (196 mg, 1.792 2H), 8.32 (d, J 4.8, mmol) 1H), 8.39 (s, 1H). (xxxii) 5-phenyl-6-(p 6-bromo-5-phenyl- Mass (400 MHz, DMSO) δ: tolylthio)-1,2,4- 1,2,4-triazin-3-amine spectroscopy: m/z 2.26 (s, 3H), 7.09 − triazin-3-amine (407 (0.50 g, 1.991 mmol) 295.2 (M+H).sup.+ (ES.sup.+), 7.15 (m, 4H), 7.44 (s, mg, 1.383 mmol, and 4- at 4.77 min, 100% 2H), 7.46 − 7.55 (m, 69.4 %) methylbenzenethiol (method B) 3H), 7.67 − 7.72 (m, (1.24 g, 9.96 mmol) 2H).

Example 4

Preparation of (i) 34(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenol; and (ii) 3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyltrifluoro-methanesulfonate

Step 1: 3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyl

[1423] 3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenol (890 mg, 85%) was prepared by demethylation of 6-(3-chloro-5-methoxyphenyl)-5-phenyl-1,2,4-triazin-3-amine (1.2 g, 3.84 mmol; vide supra) with BBr.sub.3 (5 mL) at −70° C. for 2 hours and then for a further 16 hours at RT. The resulting mixture was then poured into water (25 mL) and extracted with DCM (3×30 mL). The combined organic extracts were then dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The crude compound was purified by gradient flash chromatography, eluting with 30% ethyl acetate in hexane to afford the target compound.

[1424] HPLC purity: 96.94% (262 nm)

[1425] Mass spectroscopy: (ESI +ve) 298.9 [M+H].sup.+.

[1426] .sup.1H NMR: (400 MHz, DMSO) δ: 6.68 (m, 1H), 6.75 (m, 2H), 7.35-7.45 (m, 7H), 9.98 (s. 1H).

Step 2: 3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyl trifluoromethanesulfonate

[1427] 3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyl trifluoromethanesulfonate (2.5 g, 90%) was prepared from 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenol (1.5 g, 5.03 mmol). The alcohol was dissolved in DCM (15 mL), cooled to 0° C. and treated with triethylamine (0.66 g) for 10 minutes. Trifluoromethane sulphonyl chloride was then added at 0° C. and the mixture was warmed to RT and maintained at this temperature for 1.5 hours. The mixture then was poured into water (25 mL) and extracted with DCM (3×30 mL): the combined organic extracts were then dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude compound was used as such in the next step.

[1428] Mass spectroscopy: (ESI +ve) 431.0 [M+H].sup.+, (ESI −ve) 429.0 [M−H].sup.+.

General Procedure for Pd-Mediated Cross-Couplings of 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyltrifluoromethanesulfonate

##STR00042##

[1429] 3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyl trifluoromethanesulfonate (0.65 g, 1.51 mmol) was dissolved in DMF (10 mL) and the resulting solution was treated sequentially with LiCl (0.21 g) and a suitable organo-stannane or -boronic acid coupling partner (1.81 mmol). The resulting mixture was stirred at room temperature for 5-10 minutes then treated with palladium(0) tetrakis triphenylphosphine (0.087 g, 0.075 mmol) at reflux (90° C.) for 4-5 hours. After this time, the mixture was poured into water (25 mL) and extracted with an organic solvent such as DCM or ethyl acetate (3×30 mL). The combined organic extracts were then dried over Na.sub.2SO.sub.4, concentrated in vacuo and the isolated target compound was purified by gradient flash chromatography, eluting with ethyl acetate/hexane mixtures.

(i) 6-(3-Chloro-5-ethenylphenyl)-5-phenyl-1,2,4-triazin-3-amine

[1430] 6-(3-Chloro-5-ethenylphenyl)-5-phenyl-1,2,4-triazin-3-amine (54 mg, 11%) was prepared from 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyl trifluoromethanesulfonate (0.65 g, 1.51 mmol and tri-n-butyl(vinyl) tin (0.57 g, 1.81 mmol) according to the general procedure for Example 4.

[1431] HPLC purity: 98.35% (248 nm)

[1432] Mass spectroscopy: (ESI +ve) 309.0 [M+H].sup.+.

[1433] .sup.1H NMR: (400 MHz, DMSO) δ: 5.27 (d, 1H), 5.72 (d, 1H), 6.62 (dd, 1H), 7.23 (m, 1H), 7.44 (m, 6H), 7.51 (m, 1H), 7.57 (bs, 2H).

(ii) 6-(3-Chloro-5-cyclopropylphenyl)-5-phenyl-1,2,4-triazin-3-amine

[1434] 6-(3-Chloro-5-cyclopropylphenyl)-5-phenyl-1,2,4-triazin-3-amine (20 mg, 7%) was prepared from 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyl trifluoromethane-sulfonate (0.40 g, 0.93 mmol) and tri-n-butyl(cyclopropyl) tin (0.37 g, 1.11 mmol) according to the general procedure for Example 4.

[1435] HPLC purity: 95.98% (227 nm)

[1436] Mass spectroscopy: (ESI +ve) 322.9 [M+H].sup.+.

[1437] .sup.1H NMR: (400 MHz, CDCl3) δ: 0.47 (m, 2H), 0.87 (m, 2H), 1.36 (m, 1H), 5.58 (bs, 2H), 6.84 (s, 1H), 7.06 (s, 1H), 7.26 (s, 1H), 7.37 (m, 2H), 7.45 (m, 3H).

Example 5: Other Synthetic Methods

(i) 6-(3,5-Dichlorophenyl)-5-(3-methylpiperidin-1-yl)-1,2,4-triazin-3-amine

[1438] ##STR00043##

[1439] Step 1: Selenium dioxide (30.0 g 270 mmol) was dissolved in dioxane (450 mL) and warmed to 50° C. 3,5-Dichloroacetophenone (30.0 g, 158 mmol) was added at at this temperature and the resulting mixture was refluxed for 4 h. After completion of the reaction, the mixture was filtered through celite and concentrated in vacuo. (3,5-Dichlorophenyl)(oxo)acetic acid was isolated and purified by column chromatography, eluting with ethyl acetate/hexane mixtures (28 g, 80%).

[1440] Mass spectroscopy: (ESI −ve) 217 [M−H].sup.−

[1441] Step 2: (3,5-Dichlorophenyl)(oxo)acetic acid (28.0 g 129.0 mmol) was dissolved in ethanol (280 mL) and treated successively with a catalytic quantity of sulfuric acid and methyl hydrazinecarbimidothioate (20.5 g, 193.5 mmol). The resulting mixture was stirred for 1 hr at 78° C. After completion of the reaction (TLC), the mixture was concentrated in vacuo, poured into water (150 mL), and extracted with DCM (3×250 ml). The combined organic extracts were then dried over Na.sub.2SO.sub.4, concentrated in vacuo, and purified by gradient flash chromatography, affording 6-(3,5-dichlorophenyl)-3-(methylthio)-1,2,4-triazin-5-ol (19 g, 46%).

[1442] Mass spectroscopy: (ESI +ve) 287.9 [M−H].sup.+, (ESI −ve) 286.0 [M−H].sup.+

[1443] .sup.1H NMR: (400 MHz, DMSO) δ: 2.49 (s, 3H), 7.73 (m, 1H), 8.05 (d, 2H), 14.32 (s, 1H).

[1444] Step 3: 6-(3,5-Dichlorophenyl)-3-(methylthio)-1,2,4-triazin-5-ol (2.0 g, 6.96 mmol) was dissolved in 1,4-dioxane (20 mL) and cooled to 15° C. TEA (1.76 g, 17.4 mmol) was added drop wise to the solution, followed 5 minutes later, by methanesulfonyl chloride (1.99 g, 17.42 mmol). After stirring at room temperature for 3 hours, 6-(3,5-dichlorophenyl)-3-(methylsulfanyl)-1,2,4-triazin-5-yl methanesulfonate was detected by LCMS and the crude mixture was used directly in the next step.

[1445] Mass spectroscopy: (ESI +ve) 366.9 [M−H].sup.+

[1446] Step 4: A crude solution of 6-(3,5-dichlorophenyl)-3-(methylsulfanyl)-1,2,4-triazin-5-yl methanesulfonate (5.43 mmol) in dioxane (3 mL), was treated with K.sub.2CO.sub.3 (1.0 g, 7.2 mmol) and 3-methyl piperidine (1.68 g, 16.9 mmol), and the resulting mixture was stirred at room temperature overnight. After completion of the reaction (TLC, ethyl acetate/hexane, 1:1), the mixture was poured into water (25 mL) and extracted with DCM or ethyl acetate (3×25 ml). The combined organic extracts were then dried over Na.sub.2SO.sub.4, concentrated in vacuo and purified by flash chromatography, eluting with 15% ethyl acetate in hexane to afford 6-(3,5-dichlorophenyl)-5-(3-methylpiperidin-1-yl)-3-(methylsulfanyl)-1,2,4-triazine (0.8 g, 40%).

[1447] Mass spectroscopy: (ESI +ve) 369.0 [M+H].sup.+

[1448] .sup.1H NMR: (400 MHz, DMSO) δ: 0.67 (m, 3H), 1.07 (m, 2H), 1.35 (m, 1H), 1.53 (m, 2H), 1.67 (m, 1H), 2.45 (s, 3H), 2.74 (m, 1H), 3.64 (m, 1H), 3.76 (s, 1H), 7.60 (d, 2H), 7.64 (m, 1H).

[1449] Step 5: m-CPBA (0.654 g, 3.78 mmol) was added to a solution of a 6-(3,5-dichlorophenyl)-5-(3-methylpiperidin-1-yl)-3-(methylsulfanyl)-1,2,4-triazine (0.4 g, 1.08 mmol) in DCM (5 mL) at −15° C. and the resulting mixture was stirred at this temperature until the reaction was judged to be complete by TLC (8 hrs). The reaction was then quenched with saturated aqueous NaHCO.sub.3 solution (15 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford crude 6-(3,5-dichlorophenyl)-5-(3-methylpiperidin-1-yl)-3-(methylsulfonyl-1,2,4-triazine (1.0 g, 91%) which was used without further purification.

[1450] Step 6: A 6-(3,5-Dichlorophenyl)-5-(3-methylpiperidin-1-yl)-3-(methylsulfonyl)-1,2,4-triazine (0.25 g, 0.625 mmol) was dissolved in THF (5 mL) and the solution was purged with anhydrous NH.sub.3 gas for 1 hour. After completion of the reaction (TLC), the mixture was poured into water (15 mL) and extracted with DCM or ethyl acetate (3×15 ml). The combined organic extracts were dried over Na.sub.2SO.sub.4, concentrated in vacuo and then treated with 1N HCl solution for 10 min and extracted with ethyl acetate. The separated aqueous layer was neutralized with K.sub.2CO.sub.3 and extracted with ethyl acetate (3×150 ml); the organic phases were then dried over Na.sub.2SO.sub.4 and purified by gradient flash chromatography, affording 6-(3,5-dichlorophenyl)-5-(3-methylpiperidin-1-yl)-1,2,4-triazin-3-amine (0.01 g, 1%).

[1451] HPLC purity: 88.07% (218 nm)

[1452] Mass spectroscopy: (ESI +ve) 338.9 [M+H].sup.+

[1453] .sup.1H NMR: (400 MHz, DMSO) δ: 0.90 (m, 1H), 1.16 (m, 2H), 1.42 (m, 2H), 1.58 (s, 1H), 1.72 (m, 1H), 2.52 (m, 3H), 2.61 (m, 1H), 2.79 (m, 1H), 7.64 (s, 2H), 7.76 (s, 1H), 7.64 (bs, 2H).

(ii) 6-(6-(Methylamino)pyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine

[1454] 6-(6-(Methylamino)pyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine (49.5 mg, 0.177 mmol, 71.4%) was prepared from 5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)pyridin-2-yl(methyl)carbamate (vide supra), by BOC deprotection with trifluoroacetic acid (0.4 mL) in dichloromethane (1.6 mL) for 1 hour at room temperature.

[1455] HPLC purity: 99.7% (254 nm) at 3.45 min

[1456] Mass spectroscopy: (ESI +ve) 279.8 [M+H].sup.+

[1457] .sup.1H NMR: (400 MHz, DMSO) δ: 2.74 (d, J 4.8, 3H), 6.36 (dd, J 8.7, 0.7, 1H), 6.62-6.75 (m, 1H), 7.27 (s, 2H), 7.30 (dd, J 8.7, 2.4, 1H), 7.36-7.47 (m, 5H), 7.90 (dd, J 2.4, 0.6, 1H).

(iii) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2,6-diiodophenol

[1458] 4-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-phenol (vide supra; 140 mg, 0.530 mmol) was reacted with AcOH (2 mL) and 1-iodopyrrolidine-2,5-dione (119 mg, 0.530 mmol). The mixture was stirred at room temperature for 1 hour then concentrated in vacuo and purified by column chromatography (88 mg, 64%).

[1459] HPLC purity: 99% (254 nm) at 3.1 min

[1460] Mass spectroscopy: (ESI +ve) 517 [M+H].sup.+; (ESI −ve) 515 [M−H].sup.−

[1461] .sup.1H NMR: (400 MHz, DMSO) δ: 7.35-7.50 (m, 7H), 7.64 (s, 2H), 9.69 (s, 1H).

(iv) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-iodophenol

[1462] 4-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-phenol (vide supra; 140 mg, 0.530 mmol) was reacted with AcOH (2 mL) and 1-iodopyrrolidine-2,5-dione (119 mg, 0.530 mmol). The mixture was stirred at room temperature for 1 hour then concentrated in vacuo and purified by column chromatography (35 mg, 32%).

[1463] HPLC purity: 99% (254 nm) at 2.7 min

[1464] Mass spectroscopy: (ESI +ve) 391 [M+H].sup.+; (ESI −ve) 389 [M−H].sup.−

[1465] .sup.1H NMR: (400 MHz, DMSO) δ: 6.77 (d, J 8.4 Hz, 1H), 7.06 (dd, J 8.4, 2.2 Hz, 1H), 7.28-7.47 (m, 7H), 7.68 (d, J 2.2 Hz, 1H), 10.51 (s, 1H).

(v) 6-(3-Methoxy-5-(trifluoromethoxy)phenyl)-5-phenyl-1,2,4-triazin-3-amine

[1466] 6-(3-Methoxy-5-(trifluoromethoxy)phenyl)-5-phenyl-1,2,4-triazin-3-amine was prepared from 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-(trifluoromethoxy)phenol (100 mg, 0.287 mmol). The phenol was dissolved in THF (2 mL) and treated with iodomethane (17.87 μL, 0.287 mmol) at 0° C. After ˜15 minutes, the mixture was then allowed to warm to r.t. slowly.

[1467] Solvent was removed in vacuo; water (2 ml) and DCM (2 ml) were added and the layers were separated through a phase separator cartridge. The organic was concentrated to dryness in vacuo and purified by column chromatography (33 mg, 32%).

[1468] HPLC purity: 100% (254 nm) at 4.82 min

[1469] Mass spectroscopy: (ESI +ve) 363 [M+H].sup.+; (ESI −ve) 361 [M−H].sup.−

[1470] .sup.1H NMR: (400 MHz, DMSO) δ: 3.71 (s, 3H), 6.75-6.76 (m, 1H), 6.89-6.90 (m, 1H), 7.00-7.01 (m, 1H), 7.32-7.48 (m, 5H), 7.53 (s, 2H)

(vi) N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenyl]acetamide

Step 1: Preparation of N-(5-bromo-2-hydroxyphenyl)acetamide

[1471] 2-Amino-4-bromophenol (1 g, 5.32 mmol) was dissolved in DCM (10 mL) and cooled to 10° C. Triethylamine (0.65 g, 6.38 mmol) was then added drop-wise and stirring continued for 5 minutes before acetyl chloride (0.54 g, 6.91 mmol) was added. The reaction mixture was monitored to completion by TLC (hexane/ethyl acetate, 7:3) then quenched by saturated sodium bicarbonate solution (30 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL) and the combined organic phases were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue (0.57 g, 47%) was used in the next step without further purification.

[1472] TLC R.sub.f: 0.6 (hexane/ethyl acetate, 7:3)

[1473] Mass spectroscopy: (ESI +ve) 230.9 [M+H].sup.+, (ESI −ve) 229.0 [M+H].sup.+.

[1474] .sup.1H NMR: (400 MHz, DMSO) δ: 2.07 (s, 3H), 6.78 (d, 1H), 7.04 (d, 1H), 8.04 (d, 1H), 9.26 (s, 1H), 10.15 (s, 1H).

Step 2: Preparation of N-(5-bromo-2-methoxyphenyl)acetamide

[1475] N-(5-Bromo-2-hydroxyphenyl)acetamide (0.56 g, 2.43 mmol) was dissolved in anhydrous DMF (7.0 mL) and treated with K.sub.2CO.sub.3 (0.85 g, 6.09 mmol). The resulting mixture was heated at 70° C. for 30 minutes then treated with methyl iodide (0.69 g, 4.87 mmol). After stirring for a further 16 hours at 60° C., the reaction mixture was quenched with water (25 mL) and the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The resulting residue (0.54 g, 92%) was used in the next step without further purification.

[1476] Mass spectroscopy: (ESI +ve) 244.9 [M+H].sup.+.

[1477] TLC R.sub.f: 0.8 (hexane/ethyl acetate, 7:3)

Step 3: Preparation of N-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide

[1478] N-(5-Bromo-2-methoxyphenyl) acetamide (0.52 g, 2.13 mmol) was dissolved in DME (10 mL) and treated with palladium(II) dibenzylidene acetone (65 mg, 0.11 mmol), triphenyl phosphine (40 mg, 0.15 mmol), bis(pinacolato)diboron (0.65 g, 2.56 mmol) and potassium acetate (0.63 g, 6.4 mmol). The resulting mixture was heated at 150° C. overnight then quenched with water (30 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL) and the combined organic phases were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue (1.08 g, 91%) was used in the next step without further purification.

[1479] Mass spectroscopy: (ESI +ve) 292.1 [M+H].sup.+.

[1480] TLC R.sub.f: 0.5 (hexane/ethyl acetate, 7:3)

Step 4: Preparation of N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenyl]acetamide

[1481] N-[5-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenyl]acetamide (0.170 g, 25%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.5 g, 1.99 mmol) and N-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide according to the general procedure of Example 1.

[1482] HPLC purity: 97.62% (283 nm)

[1483] Mass spectroscopy: (ESI +ve) 336.1 [M+H].sup.+.

[1484] NMR: (400 MHz, DMSO) δ: 2.04 (s, 3H), 3.79 (s, 3H), 6.82 (d, 1H), 6.90 (d, 1H), 7.33 (m, 4H), 7.39 (m, 3H), 8.13 (s, 1H), 9.13 (s, 1H).

(vii) N-[5-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-2-hydroxyphenyl]acetamide

[1485] N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-hydroxyphenyl]acetamide was prepared by O-demethylation of N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenyl]acetamide (0.05 g, 0.15 mmol: vide supra). The methyl ether was dissolved in DCM (5 mL), cooled to −78° C. and treated with borontribromide (5.25 mmol, 1.32 g). The resulting mixture was gradually warmed to RT then stirred at this temperature for a further 16 hours. The mixture was poured into water (15 mL) and extracted with DCM (3×15 mL). The combined organic extracts were dried over Na.sub.2SO.sub.4, concentrated in vacuum and purified by gradient flash chromatography, eluting with 30% ethyl acetate in hexane to afford the target compound (0.30 g, 85%).

[1486] HPLC purity: 96.15% (219 nm)

[1487] Mass spectroscopy: (ESI +ve) 322.0 [M+H].sup.+.

[1488] .sup.1H NMR: (400 MHz, DMSO) δ: 2.05 (s, 3H), 6.71 (m, 2H), 7.43 (m, 5H), 8.00 (m, 1H), 8.49 (bs, 2H), 9.26 (s, 1H), 10.26 (bs, 1H).

(viii) 6-(2-Methyl-6-d.SUB.3.-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine

Step 1: Preparation of 2,4,6-tri(d.SUB.3.-methyl)cyclotriboroxane-pyridine Complex

[1489] A solution of trimethyl borate (10.0 mL) in THF (100 mL) was cooled under N.sub.2 to −78° C. and a solution of methyl-d.sub.3-magnesium iodide (50.0 mL, 1 M in diethyl ether, 50.0 mmol) was added drop-wise over 1 hour. After stirring at −78° C. for a further 1.5 hours 1 M aqueous HCl (25 mL) was added drop-wise over approximately 5 min and the mixture was allowed to warm to room temperature. Brine (20 mL) was added and the mixture was filtered through a short pad of celite, rinsing the celite pad with diethyl ether (50 mL). The phases were separated and the aqueous phase was extracted with diethyl ether (3×50 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL) and then concentrated in vacuo to approximately 25 mL volume. Pyridine (10 mL) was added and the light yellow solution was stirred at ambient temperature for 19.5 hours before concentration in vacuo to yield the title compound (1.39 g, crude) as a light-yellow semi-solid which was used without purification.

[1490] LCMS: m/z 214.1 [M+H].sup.+ (ESI +ve), 0.3 min (method A).

Step 2: Synthesis of 6-(2-methyl-6-d.SUB.3.-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine

[1491] A mixture of 6-(2-chloro-6-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (70.4 mg, 0.236 mmol), crude 2,4,6-tri(d.sub.3)methylcyclotriboroxane-pyridine complex (504 mg, approximately 2.36 mmol), 1 M aqueous sodium carbonate solution (0.59 mL, 0.59 mmol) and tetrakis(triphenylphosphine)palladium(0) (27.2 mg, 0.024 mmol) in 1,4-dioxane (3 mL) and water (2 mL) in a sealed vial was heated in a microwave reactor at 150° C. for 20 mins. After concentration in vacuo, DCM (10 mL) and water (10 mL) were added and the phases were separated. The aqueous phase was extracted with DCM (2×5 mL) and the combined organic phases concentrated in vacuo. Purification by gradient flash chromatography (SiO.sub.2, 5 to 40% solvent A in B. Solvent A: CH.sub.2Cl.sub.2, solvent B: 7N NH.sub.3 in MeOH/MeOH/CH.sub.2Cl.sub.2 5:5:90) yielded the title compound as a yellow solid (30.5 mg, 46%).

[1492] LCMS m/z 281.1 (M+H).sup.+ (ES.sup.+) at 2.26 min. 100% (method C).

[1493] NMR (400 MHz, CDCl.sub.3) δ: 2.47 (s, 3H), 5.44 (s, 2H), 7.02 (s, 2H), 7.33-7.39 (m, 2H), 7.43-7.49 (m, 3H).

(ix) 1-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-3,5-dimethylpyridin-4(1H)-one

Step 1: Preparation of 1-(3,5-dimethylpyridin-4-yl)-3,5-dimethylpyridinium Chloride

[1494] 3,5-lutidine (1.0 g, 9.3 mmol) was added to SOCl.sub.2 (2.0 mL, 27.9 mmol) at −10° C. The resulting mixture was heated to 120° C. and was stirred for a further two to three hours. The reaction was monitored to completion by TLC (ethyl acetate/hexane, 1:1) then precipitated with ethyl acetate. The desired product was collected by filtration and used in the next step without further purification (1.79 g, 90%).

[1495] Mass: (ESI +ve) 214.1 [M+H].sup.+

[1496] TLC R.sub.f: 0.05 (methanol/chloroform, 3:7).

Step 2: Preparation of 3,5-dimethylpyridin-4-ol

[1497] 1-(3,5-dimethylpyridin-4-yl)-3,5-dimethylpyridinium chloride (1.0 g, 4.7 mmol) and anhydrous H.sub.3PO.sub.3 (0.97 g, 11.7 mmol) were heated, as a neat mixture, to 150-160° C. in a sealed tube for 8 hours with TLC monitoring (methanol/chloroform 5:5). Upon completion of the reaction, the mixture was diluted with ethanol and acetone (1:1, 50 mL), filtered and concentrated under vacuum. The product was purified employing Dowex 50 resin.

[1498] Mass: (ESI +ve) 124.0 [M+H].sup.+

[1499] TLC R.sub.f: 0.38 (methanol/chloroform, 2:8).

Step 3: Preparation of 1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-3,5-dimethylpyridin-4(1H)-one

[1500] 1-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-3,5-dimethylpyridin-4(1H)-one (40 mg, 5%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.70 g, 2.7 mmol), 3,5-dimethylpyridin-4-ol (0.45 g, 3.7 mmol) and K.sub.2CO.sub.3 (0.93 g, 6.7 mmol) according to the general procedure of Example 3.

[1501] HPLC purity: 92.33% (286 nm)

[1502] Mass spectroscopy: (ESI +ve) 294.1 [M+H].sup.+

[1503] .sup.1H NMR: (400 MHz, CDCl3) δ:1.77 (s, 6H), 7.44 (m, 5H), 7.66 (s, 2H), 7.74 (bs, 2H).

(x) 6-[2-(Azetidin-1-yl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine

[1504] 6-[2-(Azetidin-1-yl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine was prepared from 5-phenyl-6-(2-chloro-6-methyl-pyridin-4-yl)-1,2,4-triazin-3-amine (100 mg, 0.34 mmol) and azetidine (96 mg, 0.11 ml, 1.69 mmol) according to the general procedure for Preparation 4a.

[1505] LCMS: (ES.sup.+) 319.1 (M+H).sup.+ at 4.02 min, 99% (method C).

[1506] .sup.1H NMR: (400 MHz, DMSO) δ: 2.22 (s, 3H), 2.22-2.28 (m, 2H), 3.76 (t, J 7.3, 4H), 5.99 (s, 1H), 6.47 (s, 1H), 7.39-7.50 (m, 5H), 7.52 (bs, 2H).

(xi) 6-[2-(azetidin-1-yl)-6-methylpyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine

[1507] 6-[2-(azetidin-1-yl)-6-methylpyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (6.0 mg, 4%) was prepared from 5-(4-fluorophenyl)-6-(2-chloro-6-methyl-pyridin-4-yl)-1,2,4-triazin-3-amine (150 mg, 0.48 mmol) and azetidine (136 mg, 0.16 ml, 2.38 mmol) according to the general procedure for Preparation 4a.

[1508] LCMS: (ES.sup.+) 337.1 (M+H).sup.+ at 4.18 min, 97% (method C).

[1509] .sup.1H NMR: (400 MHz, DMSO) δ: 2.23 (s, 3H), 2.24-2.30 (m, 2H), 3.79 (t, J 7.6, 4H), 6.52 (s, 1H), 6.86 (s, 1H), 7.24-7.29 (m, 2H), 7.48-7.50 (m, 2H), 7.55 (bs, 2H).

(xii) 6-[2-(Azetidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine

[1510] 6-[2-(Azetidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine (20.0 mg, 19%) was prepared from 5-phenyl-6-(2-chloro-6-trifluoromethyl-pyridin-4-yl)-1,2,4-triazin-3-amine (100 mg, 0.28 mmol) and azetidine according to the general procedure for Preparation 4a.

[1511] LCMS: (ES.sup.+) 373.0 (M+H).sup.+ at 4.52 min, 99% (method C).

[1512] .sup.1H NMR: (400 MHz, DMSO) δ: 2.27-2.35 (m, 2H), 3.89 (t, J 7.5, 4H), 6.03 (s, 1H), 6.46 (s, 1H), 7.41-7.53 (m, 5H), 7.69 (br. s, 2H).

[1513] The compounds of Examples 1 to 5 were found to possess activity in biological tests described above. Biological activity determined by Test A includes IC.sub.50 and pKi values for human A.sub.2a and A.sub.1 receptors, and the compounds of Examples 1 to 5 were found to possess pKi values in excess of 5 (or 6) vs. at least one of these receptors (for example as illustrated for certain compounds in the table below).

TABLE-US-00011 Example no. pKi A2a pki A1 1(vi) 7.29 7.25 1(ix) 7.70 7.81 1(xiii) 8.40 7.36 1(xv) 7.11 8.45 1(xviii) 6.75 6.91 1(xxiv) 6.97 8.03 1(xxx) 6.30 ND 1(xxxv) 7.19 8.20 1(xli) 8.68 7.83 1(xlii) 8.86 9.84 1(xliii) 7.74 8.54 1(li) 8.66 6.87 1(lvi) 8.22 7.33 1(lxxii) 6.99 8.52 1(lxxvii) 8.11 7.29 1(lxxix) 7.45 9.35 1(lxxx) 6.61 6.01 1(xc) 8.07 7.26 1(xcv) 7.86 6.67 1(cxxxiv) 5.62 7.62 1(cxlvi) 6.31 7.40 1(cliv) 7.56 6.77 1(clviii) 7.98 6.96 1(clix) 7.81 7.07 1(clxix) 8.40 6.99 1(clxxiv) 8.07 6.89 1(clxxvi) 8.03 6.93 1(clxxix) 8.62 7.52 1(clxxx) 8.90 7.76 1(clxxxi) 8.71 7.17 1(cxci) 8.26 7.36 1(cxciii) 8.34 6.93 1(cciv) 7.21 5.97 1(ccix) 8.59 7.60 1(ccxi) 7.71 8.74 1(ccxii) 8.66 7.68 1(ccxiii) 7.51 7.12 1(ccxviii) 6.58 5.25 2(iii) 7.31 5.37 2(iv) 7.79 <5 2(vi) 7.39 <5 2(xxii) 5.07 6.71 2(xxv) 5.53 7.49 3(i) 7.17 <5 3(v) 5.96 ND 3(xvi) 7.41 7.15 3(xxi) 6.22 8.07 3(xxiv) 7.39 8.46 3(xxxii) 5.82 7.00 4(ii) 7.89 7.43 5(vii) 6.73 8.69 5(viii) 7.91 7.26 5(ix) 7.77 7.62 5(x) 8.52 8.05 5(xi) 7.76 6.90

Example 7

[1514] The compounds of Example 1(vi) and Example 1 (xliii) (dose of 2-10 mg/kg or 0.3-3 mg/kg, p.o., respectively; 120 min pre-test time) were found to reverse cataleptic behaviour in rats pre-treated with haloperidol in a dose-dependent manner with an ED.sub.50 of 9.8 and 0.27 mg/kg (p.o.), respectively, using the procedure described in Test B above. In a similar manner, the compounds of Examples 1(xiii), 1(li), 1(lvi), 1(lxxvii), 1(xc), 1(xcv), 1(cliv), 1(clviii), 1(clix), 1(ccix), 1(cxci), 1(cxciii), 1(clxix), 1(clxxix), 1(clxxxiv), 1(ccxii) and 5(x) were found to reverse cataleptic behavior in rats pre-treated with haloperidol in a statistically significant manner at a dose of 1 mg/kg (p.o.) (with a 120 min pre-test time, according to Test B above.

Abbreviations

[1515] m-CPBA=m-chloroperoxybenzoic acid [1516] bmim=1-butyl-3-methylimidazolium [1517] DCM=dichloromethane [1518] DME=dimethoxyethane [1519] DMF=dimethylformamide [1520] DMSO=dimethylsulfoxide [1521] ESI=electro spray ionisation [1522] EtOAc=Ethyl acetate [1523] FT=fourier transform [1524] HPLC=high performance liquid chromatography [1525] IR=infra-red [1526] LC=liquid chromatography [1527] MS=mass spectrometry [1528] NMP=N-methyl pyrrolidinone [1529] NMR=nuclear magnetic resonance [1530] rt=room temperature [1531] THF=tetrahydrofuran [1532] TLC=thin layer chromatography

[1533] Prefixes n-, s-, i-, t- and tert-have their usual meanings: normal, secondary, iso, and tertiary.