Substituted benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepines as GABA A GAMMA1 positive allosteric modulators

Abstract

Compounds having the general formula (I) ##STR00001##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and X are as described herein, compositions including the compounds and methods of using the compounds.

Claims

1. A compound, wherein the compound is selected from the group consisting of: ##STR00068## ##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078## ##STR00079## ##STR00080## ##STR00081## ##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094## ##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099## ##STR00100## ##STR00101## ##STR00102## ##STR00103## ##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108## ##STR00109## ##STR00110## and ##STR00111## or a pharmaceutically acceptable salt thereof.

2. A The compound according to claim 1, wherein the compound is ##STR00112## or a pharmaceutically acceptable salt thereof.

Description

EXAMPLES

(1) Building Block A

7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one

(2) ##STR00009##

a) 5-chloro-2-methyl-3,1-benzoxazin-4-one

(3) A solution of 2-amino-6-chlorobenzoic acid (250 g, 1.46 mol) in acetic anhydride (1250 mL) was stirred at 140° C. for 2 h. The reaction mixture was concentrated in vacuo. The resulting crude residue was suspended in ethyl acetate (1000 mL), stirred for 30 min, filtered and dried in vacuo to afford the title compound (238 g, 84%) as a grey solid. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ: 7.80 (app t, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 2.36 (s, 3H).

b) N-[3-chloro-2-(2,6-difluorobenzoyl)phenyl]acetamide

(4) To a solution of 5-chloro-2-methyl-3,1-benzoxazin-4-one (100 g, 511.2 mmol) and 2-bromo-1,3-difluorobenzene (118.4 g, 613.5 mmol) in tetrahydrofuran (1000 mL) was added dropwise i-PrMgCl.Math.LiCl (1.3 M, 500 mL, 650 mmol) at −70° C. under nitrogen. The mixture was allowed to warm up to room temperature within 1 h, quenched with saturated aqueous ammonium chloride (1500 mL) and extracted with ethyl acetate (2×1500 mL). The organic phase was washed with brine (2000 mL), dried over sodium sulfate and concentrated in vacuo. The residue was suspended in ethyl acetate (150 mL). The resulting suspension was stirred at room temperature for 20 min, filtered and dried in vacuo to afford the title compound (113 g, 71%) as an off-white solid. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ: 9.85 (s, 1H), 7.65-7.45 (m, 1H), 7.40 (t, J=7.2 Hz, 1H), 7.38-7.34 (m, 2H), 7.16 (t, J=8.8 Hz, 2H), 1.85 (s, 3H).

c) (2-amino-6-chloro-phenyl)-(2,6-difluorophenyl)methanone

(5) To a solution of N-[3-chloro-2-(2,6-difluorobenzoyl)phenyl]acetamide (113 g, 364.9 mmol) in ethanol (250 mL) was added aqueous hydrochloric acid (12 M, 200 mL). The reaction mixture was stirred at 100° C. for 1 h, then diluted with ethyl acetate (1100 mL). The organic phase was washed with water (1100 mL), saturated aqueous sodium bicarbonate (1100 mL) and brine (1100 mL), dried over sodium sulfate and concentrated in vacuo. Petroleum ether (120 mL) was added to the crude and the suspension was stirred at room temperature for 20 min. The solid was filtered and dried to afford the title compound (88 g, 90%) as a yellow solid. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): δ: 7.62-7.56 (m, 1H), 7.21-7.15 (m, 3H), 6.83 (d, J=7.6 Hz, 1H), 6.74 (s, 2H), 6.58 (d, J=7.6 Hz, 1H).

d) (6-amino-3-bromo-2-chloro-phenyl)-(2,6-difluorophenyl)methanone

(6) To a solution of (2-amino-6-chloro-phenyl)-(2,6-difluorophenyl)methanone (88.0 g, 328.8 mmol) in dichloromethane (225 mL) and N,N-dimethylformamide (225 mL) was added 1-bromopyrrolidine-2,5-dione (64.4 g, 362 mmol) at 0° C. The reaction mixture was stirred at 30° C. for 1 h. The mixture was diluted with dichloromethane (600 mL) and washed with water (500 mL) and brine (4×500 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica, petroleum ether/ethyl acetate, 1:0 to 2:1). The solid was suspended in petroleum ether (200 mL) and stirred at room temperature for 20 min. The suspension was filtered and the solid was dried in vacuo to afford the title compound (96.0 g, 84%) as a yellow solid. MS: 345.9 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 347.8 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

e) 7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one

(7) To a solution of (6-amino-3-bromo-2-chloro-phenyl)-(2,6-difluorophenyl)methanone (25.0 g, 72.1 mmol) in pyridine (625 mL) was added ethyl 2-aminoacetate hydrochloride (70.5 g, 505 mmol). The reaction mixture was stirred at 135° C. for 36 h. The reaction mixture was concentrated in vacuo to remove pyridine. The residue was diluted with ethyl acetate (2000 mL) and washed with HCl (1.0 M, 3×1500 mL), water (2000 mL) and brine (2×1000 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica, petroleum ether/ethyl acetate 10:1 to 2:1) to afford the title compound (10.1 g, 12%) as an off-white solid. MS: 385.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), ESI pos.

(8) Building Block B

7-bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one

(9) ##STR00010##

a) N-[3-chloro-2-(2-fluorobenzoyl)phenyl]acetamide

(10) To a solution of 5-chloro-2-methyl-3,1-benzoxazin-4-one (20.0 g, 102.3 mmol) and 1-bromo-2-fluorobenzene (17.9 g, 102.3 mmol) in tetrahydrofuran (600 mL) at −70° C. was added dropwise n-BuLi in tetrahydrofuran (2.5 M, 49 mL, 123 mmol). The reaction mixture was stirred at −60° C. for 1 h, then quenched with aqueous ammonium chloride (200 mL). The aqueous layer was extracted with tetrahydrofuran (2×250 mL) and ethyl acetate (2×250 mL). The combined organic phase was washed with brine (200 mL), dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica, petroleum ether/ethyl acetate 20:1 to 3:1) afforded the title compound (21 g, 70%) as a white solid. MS: 292.3 ([M+H]+), ESI pos.

b) (2-amino-6-chloro-phenyl)-(2-fluorophenyl)methanone

(11) In analogy to experiment of building block A c, N-[3-chloro-2-(2-fluorobenzoyl)phenyl]acetamide was converted into the title compound (10 g, 58%) which was obtained as a yellow solid. MS: 250.1 ([M+H]+), ESI pos.

c) (6-amino-3-bromo-2-chloro-phenyl)-(2-fluorophenyl)methanone

(12) In analogy to experiment of building block A d, (2-amino-6-chloro-phenyl)-(2-fluorophenyl)methanone was converted into the title compound (32.4 g, 70%) which was obtained as a yellow solid. MS: 327.9 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 330.0 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

d) 7-bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one

(13) To a solution of (6-amino-3-bromo-2-chloro-phenyl)-(2-fluorophenyl)methanone (35.0 g, 98.3 mmol) in pyridine (210 mL) was added ethyl 2-aminoacetate hydrochloride (96.0 g, 688 mmol) at 90° C. The reaction mixture was stirred at 110° C. for 16 h. The reaction mixture was cooled down to room temperature and most of pyridine was removed in vacuo. The residue was diluted with ethyl acetate (1250 mL). The organic phase was washed with aqueous HCl (1.0 M, 1250 mL), water (500 mL) and brine (1000 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by flash column chromatography (silica, petroleum ether/ethyl acetate 1:0, 25:1, 1:1). The product was dissolved in ethyl acetate (15 mL). Petroleum ether (45 mL) was added dropwise to get a white slurry. The solid was collected by filtration and dried in vacuo to afford the title compound (30.4 g, 39%) as an off-white solid. MS: 367.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 368.9 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

(14) Building Block G

(rac)-7-bromo-6-chloro-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

(15) ##STR00011##

a) (rac)-tert-butyl N-[2-[4-bromo-3-chloro-2-(2-fluorobenzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamate

(16) To a solution of (6-amino-3-bromo-2-chloro-phenyl)-(2-fluorophenyl)methanone (2.0 g, 6.09 mmol) and 2-(tert-butoxycarbonylamino)propanoic acid (1.73 g, 9.13 mmol) in pyridine (20 mL) was added phosphoryl chloride (1.22 g, 7.98 mmol) slowly at −5° C. The reaction mixture was stirred at −5° C. for 1 h, before being slowly poured into water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic phase was washed with brine (2×50 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate 5:1) to afford the title compound (2.95 g, 97%) as a yellow solid. MS: 399.1 ([{.sup.79Br, .sup.35Cl}M-C.sub.4H.sub.8—CO.sub.2+H].sup.+), 401.0 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M-C.sub.4H.sub.8—CO.sub.2+H].sup.+), ESI pos.

b) (rac)-2-amino-N-[4-bromo-3-chloro-2-(2-fluorobenzoyl)phenyl]propanamide

(17) To a solution of (rac)-tert-butyl N-[2-[4-bromo-3-chloro-2-(2-fluorobenzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamate (2.9 g, 5.8 mmol) in dichloromethane (14.5 mL) was slowly added hydrochloric acid (4.0 wt in dioxane, 14.5 mL, 58.0 mmol). The reaction mixture was stirred at 25° C. for 2 h. Saturated aqueous sodium bicarbonate was added slowly until pH>8, then the mixture was extracted with dichloromethane (3×100 mL). The combined organic phase was washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to afford the title compound (2.2 g, 92%) as a yellow oil. MS: 399.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 401.0 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

c) (rac)-7-bromo-6-chloro-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

(18) To a solution of (rac)-2-amino-N-[4-bromo-3-chloro-2-(2-fluorobenzoyl)phenyl]propanamide (2.2 g, 5.5 mmol) in ethanol (20 mL) was added acetic acid (4 mL). The reaction mixture was stirred at 80° C. for 16 h, then concentrated in vacuo. The formed crystals were filtered, purified by trituration with ethyl acetate (15 mL), then collected by filtration and dried in vacuo to afford the title compound (1.6 g, 76%) as a yellow solid. MS: 381.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 383.0 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

(19) Building Block L

(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

(20) ##STR00012##

a) tert-butyl N-[(1S)-2-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamate

(21) In analogy to experiment of building block G a, (6-amino-3-bromo-2-chloro-phenyl)-(2,6-difluorophenyl)methanone using (2S)-2-(tert-butoxycarbonylamino)propanoic acid was converted into the title compound (1.50 g, 98%) which was obtained as a yellow solid. MS: 418.7 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M-C.sub.4H.sub.8—CO.sub.2+H].sup.+), 540.7 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+Na].sup.+), ESI pos.

b) (2S)-2-amino-N-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]propanamide

(22) In analogy to experiment of building block G b, tert-butyl N-[(1S)-2-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamate was converted into the title compound (1.1 g, 94%) which was obtained as a yellow oil, which was used as such in the following step without further characterization.

c) (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

(23) To a solution of (2S)-2-amino-N-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]propanamide (960 mg, 2.30 mmol) in toluene (9.19 mL) was added silica (138 mg, 2.30 mmol). The reaction mixture was stirred at 90° C. for 15 h, then concentrated in vacuo. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate 3:1) to afford the title compound (920 mg, 95%) as a yellow solid. MS: 399.1 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 401.1 ([{.sup.79Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

(24) Building Block M

(3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

(25) ##STR00013##

a) tert-butyl N-[(1S)-2-[3,4-dichloro-2-(2,6-difluorobenzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamate

(26) In analogy to experiment of building block G a, (6-amino-2,3-dichloro-phenyl)-(2,6-difluorophenyl)methanone using (2S)-2-(tert-butoxycarbonylamino)propanoic acid was converted into the title compound (5.0 g, 64%) which was obtained as a yellow foam. The crude was used as such in the following step without further characterization.

b) (2S)-2-amino-N-[3,4-dichloro-2-(2,6-difluorobenzoyl)phenyl]propanamide

(27) In analogy to experiment of building block G b, tert-butyl N-[(1S)-2-[3,4-dichloro-2-(2,6-difluorobenzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamate was converted into the title compound (3.6 g, 91%) which was obtained as a yellow oil. MS: 373.0 ([{.sup.35Cl, .sup.35Cl}M+H].sup.+), ESI pos.

c) (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

(28) In analogy to experiment of building block L c, (2S)-2-amino-N-[3,4-dichloro-2-(2,6-difluorobenzoyl)phenyl]propanamide was converted into the title compound (3.20 g, 93%) which was obtained as a yellow foam. MS: 355.0 ([{.sup.35C1, .sup.35Cl}M+H].sup.+), ESI pos.

(29) Building Block O

(3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

(30) ##STR00014##

a) tert-butyl N-[(1S)-2-[3,4-dichloro-2-(3-fluoropyridine-2-carbonyl)anilino]-1-methyl-2-oxo-ethyl]carbamate

(31) In analogy to experiment of building block G a, N-[3,4-dichloro-2-(3-fluoropyridine-2-carbonyl)phenyl]acetamide using (2S)-2-(tert-butoxycarbonylamino)propanoic acid was converted into the title compound (8.6 g, 67%) as a white solid. MS: 456.0 ([{.sup.35Cl, .sup.35Cl}M+H].sup.+), ESI pos.

b) (2S)-2-amino-N-[3,4-dichloro-2-(3-fluoropyridine-2-carbonyl)phenyl]propanamide

(32) In analogy to experiment of building block G b, tert-butyl N-[(1S)-2-[3,4-dichloro-2-(3-fluoropyridine-2-carbonyl)anilino]-1-methyl-2-oxo-ethyl]carbamate was converted into the title compound (6.6 g, 100%) which was obtained as a yellow solid. MS: 356.0 ([{.sup.35Cl, .sup.35Cl}M+H].sup.+), ESI pos.

c) (3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

(33) In analogy to experiment of building block L c, (2S)-2-amino-N-[3,4-dichloro-2-(3-fluoropyridine-2-carbonyl)phenyl]propanamide was converted into the title compound (5.5 g, 88%) which was obtained as a yellow solid. MS: 338.0 ([{.sup.35Cl, .sup.35Cl}M+H].sup.+), ESI pos.

(34) Building Block Q

(3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

(35) ##STR00015##

a) N-[3-bromo-4-chloro-2-(2,6-difluorobenzoyl)phenyl]acetamide

(36) In analogy to experiment of building block A d, N-(3-bromo-2-(2,6-difluorobenzoyl)phenyl)acetamide using 1-chloropyrrolidine-2,5-dione was converted into the title compound (10.1 g, 70%) which was obtained as a light yellow solid. MS: 388.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 390.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

b) (6-amino-2-bromo-3-chloro-phenyl)-(2,6-difluorophenyl)methanone

(37) In analogy to experiment of building block A c, N-[3-bromo-4-chloro-2-(2,6-difluorobenzoyl)phenyl]acetamide was converted into the title compound (8.2 g, 92%) which was obtained as a yellow solid. MS: 346.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 348.0 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

c) tert-butyl N-[(1S)-2-[3-bromo-4-chloro-2-(2,6-difluorobenzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamate

(38) In analogy to experiment of building block G a, (6-amino-2-bromo-3-chloro-phenyl)-(2,6-difluorophenyl)methanone using (2S)-2-(tert-butoxycarbonylamino)propanoic acid was converted into the title compound (8.64 g, 69%) which was obtained as a yellow solid. MS: 515.2 ([{.sup.79Br, .sup.35Cl}M−H].sup.−, 517.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M−H].sup.−) ESI neg.

d) (2S)-2-amino-N-[3-bromo-4-chloro-2-(2,6-difluorobenzoyl)phenyl]propanamide

(39) In analogy to experiment of building block G b, tert-butyl N-[(1S)-2-[3-bromo-4-chloro-2-(2,6-difluorobenzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamate was converted into the title compound (6.27 g, 90%) which was obtained as a light brown oil. MS: 417.1 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 419.0 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

e) (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

(40) In analogy to experiment of building block L c, (2S)-2-amino-N-[3-bromo-4-chloro-2-(2,6-difluorobenzoyl)phenyl]propanamide was converted into the title compound (3.98 g, 68%) which was obtained as a yellow solid. MS: 399.1 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 401.0 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

(41) Building Block R

(3S)-7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

(42) ##STR00016##

a) tert-butyl N-[(1S)-2-[4-bromo-3-chloro-2-(3-fluoropyridine-2-carbonyl)anilino]-1-methyl-2-oxo-ethyl]carbamate

(43) In analogy to experiment of building block G a, (6-amino-3-bromo-2-chloro-phenyl)-(3-fluoro-2-pyridyl)methanone using (2S)-2-(tert-butoxycarbonylamino)propanoic acid was converted into the title compound (1.4 g, 97%) which was obtained as a yellow foam. The crude was used as such in the following step without further characterization.

b) (2S)-2-amino-N-[4-bromo-3-chloro-2-(3-fluoropyridine-2-carbonyl)phenyl]propanamide

(44) In analogy to experiment of building block G b, tert-butyl N-[(1S)-2-[4-bromo-3-chloro-2-(3-fluoropyridine-2-carbonyl)anilino]-1-methyl-2-oxo-ethyl]carbamate was converted into the title compound (1.1 g, 98%) which was obtained as a yellow oil. The crude was used as such in the following step without further characterization.

c) (3S)-7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

(45) In analogy to experiment of building block L c, (2S)-2-amino-N-[4-bromo-3-chloro-2-(3-fluoropyridine-2-carbonyl)phenyl]propanamide was converted into the title compound (430 mg, 40%) which was obtained as a yellow solid. MS: 381.9 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 383.9 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

(46) Building Block S

(3S)-6-chloro-5-(2,6-difluorophenyl)-7-iodo-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

(47) ##STR00017##

a) tert-butyl N-[(1S)-2-[3-chloro-2-(2,6-difluorobenzoyl)-4-iodo-anilino]-1-methyl-2-oxo-ethyl]carbamate

(48) In analogy to experiment of building block G a, (6-amino-2-chloro-3-iodo-phenyl)-(2,6-difluorophenyl)methanone using (2S)-2-(tert-butoxycarbonylamino)propanoic acid was converted into the title compound (5.8 g, 81%) which was obtained as a yellow solid. MS: 465.0 ([M-C.sub.4H.sub.8—CO.sub.2+H].sup.+), 509.0 ([M-C4H.sub.8+H].sup.+), ESI pos.

b) (2S)-2-amino-N-[3-chloro-2-(2,6-difluorobenzoyl)-4-iodo-phenyl]propanamide

(49) In analogy to experiment of building block G b, tert-butyl N-[(1S)-2-[3-chloro-2-(2,6-difluorobenzoyl)-4-iodo-anilino]-1-methyl-2-oxo-ethyl]carbamate was converted into the title compound (4.7 g, 99%) which was obtained as a yellow solid. The crude was used as such in the following step without further characterization.

c) (3S)-6-chloro-5-(2,6-difluorophenyl)-7-iodo-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

(50) In analogy to experiment of building block L c, (2S)-2-amino-N-[3-chloro-2-(2,6-difluorobenzoyl)-4-iodo-phenyl]propanamide was converted into the title compound (3.8 g, 94%) which was obtained as a yellow solid. MS: 446.8 ([M+H].sup.+), ESI pos.

(51) Building Block T

(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepin-2-one

(52) ##STR00018##

a) tert-butyl N-[(1S)-[[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]carbamoyl]propyl]carbamate

(53) In analogy to experiment of building block G a, (6-amino-3-bromo-2-chloro-phenyl)-(2,6-difluorophenyl)methanone using (2S)-2-(tert-butoxycarbonylamino)butanoic acid was converted into the title compound (1.08 g, 68%) which was obtained as a yellow solid. MS: 433.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M-C.sub.4H.sub.8—CO.sub.2+H].sup.+), 477.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M-C.sub.4H.sub.8+H].sup.+), ESI pos.

b) (2S)-2-amino-N-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]butanamide

(54) In analogy to experiment of building block G b, tert-butyl N-[(1S)-1-[[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]carbamoyl]propyl]carbamate was converted into the title compound (730 mg, 90%) which was obtained as a yellow oil. MS: 433.0 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

c) (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepin-2-one

(55) In analogy to experiment of building block L c, (2S)-2-amino-N-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]butanamide was converted into the title compound (650 mg, 97%) which was obtained as a light brown foam. MS: 414.9 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

(56) Building Block U

(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl)-1,3-dihydro-1,4-benzodiazepin-2-one

(57) ##STR00019##

a) tert-butyl N-[(1S)-2-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)anilino]-1-(methoxymethyl)-2-oxo-ethyl]carbamate

(58) In analogy to experiment of building block G a, (6-amino-3-bromo-2-chloro-phenyl)-(2,6-difluorophenyl)methanone using (2S)-2-(tert-butoxycarbonylamino)-3-methoxy-propanoic acid was converted into the title compound (4.3 g, 85%) which was obtained as a yellow solid. The crude was used as such in the following step without further characterization.

b) (2S)-2-amino-N-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]-3-methoxy-propanamide

(59) In analogy to experiment of building block G b, tert-butyl N-[(1S)-2-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)anilino]-1-(methoxymethyl)-2-oxo-ethyl]carbamate was converted into the title compound (3.0 g, 96%) which was obtained as a yellow oil. MS: 447.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 449.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

c) (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl)-1,3-dihydro-1,4-benzodiazepin-2-one

(60) In analogy to experiment of building block L c, (2S)-2-amino-N-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]-3-methoxy-propanamide was converted into the title compound (1.9 g, 78%) which was obtained as a white solid. The crude was used as such in the following step without further characterization. MS: 429.1 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 431.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 30

(4S)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(61) ##STR00020##

a) (rac)-7-bromo-6-chloro-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione

(62) To a suspension of (rac)-7-bromo-6-chloro-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (building block G, 500 mg, 1.31 mmol) in toluene (8.33 mL) at room temperature was added Lawesson's reagent (635 mg, 1.57 mmol). The reaction mixture was stirred at 110° C. for 1 h, before being concentrated in vacuo. The crude material was purified by flash column chromatography (silica, 15-25% ethyl acetate in heptane) to afford the title compound (820 mg, 91%) which was obtained as a yellow solid. The crude was used as such in the following step without further characterization.

b) (rac)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(63) To a solution of (rac)-7-bromo-6-chloro-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione (240 mg, 0.600 mmol) in butan-1-ol (3.2 mL) was added formohydrazide (108 mg, 1.81 mmol). The reaction mixture was stirred at 120° C. for 16 h. The mixture was diluted with dichloromethane (20 mL), washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (TFA) to afford the title compound (250 mg, 100%) which was obtained as a white solid. MS: 404.8 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 406.7 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

c) (4S)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(64) (rac)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (254 mg, 0.630 mmol) was purified by SFC (Chiralcel OJ-3, 0.05% diethylamine in methanol, 5-40%) affording:

(65) (−)-enantiopure (S)-title compound (88.1 mg) as a white solid. MS: 404.8 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 406.8 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

(66) (+)-enantiopure (R)-title compound (80.4 mg) as a white solid. MS: 404.9 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 406.8 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 31

8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-ol

(67) ##STR00021##

a) 7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-thione

(68) To a suspension of 7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block A, 6.7 g, 17.4 mmol) in toluene (167 mL) at room temperature was added Lawesson's reagent (8.43 g, 20.9 mmol). The reaction mixture was stirred at 120° C. for 1.5 h, before being diluted with ethyl acetate (400 mL). The organic layer was washed with water (300 mL) and brine (300 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (silica, 15-30% ethyl acetate in heptane) to afford the title compound (6.98 g, 100%) as a yellow solid. MS: 400.8 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 402.9 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

b) 8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(69) In analogy to experiment of example 30 b, 7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-thione using formohydrazide was converted into the title compound (2.4 g, 32%) which was obtained as a white solid. MS: 409.1 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 411.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

c) 8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-ol

(70) To a solution of sodium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 0.37 mL, 0.370 mmol) in tetrahydrofuran (5 mL) was added 8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (100.0 mg, 0.240 mmol) at −65° C. The mixture was stirred at −65° C. for 30 min, then 2-(benzenesulfonyl)-3-phenyl-oxaziridine (97 mg, 0.370 mmol) was added. The reaction mixture was stirred at −65° C. for 2 h, before being quenched by addition of saturated aqueous ammonium chloride. The aqueous phase was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (2×30 mL), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Boston Prime C18, 0.1% trifluoroacetic acid in water/acetonitrile) followed by chiral-HPLC (Daicel Chiralcel OJ-H, methanol) to afford the title compound (30 mg, 29%) as a white solid. MS: 424.9 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 426.8 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 32

(4S)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(71) ##STR00022##

a) (rac)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(72) In analogy to experiment of example 30 b, (rac)-7-bromo-6-chloro-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using pyridazine-3-carbohydrazide was converted into the title compound (220 mg, 75%) which was obtained as a white solid. MS: 482.9 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 484.8 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

b) (4S)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(73) (rac)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (220 mg, 0.450 mmol) was purified by SFC (Chiralcel OJ-3, 0.05% diethylamine in methanol, 5-40%), followed by lyophilization affording:

(74) (−)-enantiopure (S)-title compound (64.3 mg) as a white solid. MS: 483.1 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 485.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

(75) (+)-enantiopure (R)-title compound (61.4 mg) as a white solid. MS: 483.1 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 485.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 35

8-bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-01

(76) ##STR00023##

a) 7-bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione

(77) In analogy to experiment of example 30 a, 7-bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one was converted into the title compound (390 mg, 54%) which was obtained as a yellow solid. The crude was used as such in the following step without further characterization.

b) 8-bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(78) In analogy to experiment of example 30 b, 7-bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione using pyridazine-3-carbohydrazide was converted into the title compound (294 mg, 73%) which was obtained as a white solid. MS: 469.1 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 471.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

c) [8-bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetate

(79) To a solution of 8-bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (100 mg, 0.21 mmol) in acetic acid (2 mL) was added iodine (27 mg, 0.11 mmol), potassium acetate (42 mg, 0.43 mmol) and potassium persulfate (58 mg, 0.21 mmol). The reaction mixture was heated to 90° C. for 12 h, before being quenched by addition of saturated aqueous Na.sub.2SO.sub.3 (10 mL). The mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with water (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica, dichloromethane/methanol 100:1 to 80:1) to afford the title compound (55 mg, 49%) as a white solid. MS: 526.9 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 528.9 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

d) 8-bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-ol

(80) To a solution of [8-bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetate (55 mg, 0.10 mmol) in ethanol (2.75 mL) was added sodium carbonate (22 mg, 0.21 mmol). The reaction mixture was stirred at room temperature for 4 h, then filtered and concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane/methanol), followed by preparative HPLC (Shim-pack C18, 0.225% trifluoroacetic acid in water/acetonitrile) and lyophilized to afford the title compound (13.1 mg, 26%) as a white solid. MS: 485.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 487.0 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 51

(4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(81) ##STR00024##

a) (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione

(82) In analogy to experiment of example 30 a, (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (building block L) was converted into the title compound (410 mg, 96%) which was obtained as a yellow solid. MS: 415.1 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 417.0 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

b) (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(83) In analogy to experiment of example 30 b, (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using formohydrazide was converted after chiral purification into the (−)-enantiopure (S)-title compound (66 mg, 43%) which was obtained as a white solid. MS: 423.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 425.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 52

(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(84) ##STR00025##

a) (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione

(85) In analogy to experiment of example 30 a, (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (building block M) was converted into the title compound (4.2 g, 90%) which was obtained as a yellow solid. The crude was used as such in the following step without further characterization.

b) (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(86) In analogy to experiment of example 30 b, (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using pyrimidine-4-carbohydrazide was converted after chiral purification into the (−)-enantiopure (S)-title compound (71.6 mg, 31%) which was obtained as a white solid. MS: 456.9 ([{.sup.35Cl, .sup.35Cl}M+H].sup.+), ESI pos.

Example 53

(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(87) ##STR00026##

(88) In analogy to experiment of example 30 b, (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using 1-methylpyrazole-4-carbohydrazide was converted after chiral purification into the (−)-enantiopure (S)-title compound (60.8 mg, 29%) which was obtained as a white solid. MS: 459.1 ([{.sup.35Cl, .sup.35Cl}M+H].sup.+), ESI pos.

Example 56

(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(89) ##STR00027##

(90) In analogy to experiment of example 30 b, (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using pyridazine-3-carbohydrazide was converted after chiral purification into the (−)-enantiopure (S)-title compound (80.0 mg, 21%) which was obtained as a white solid. MS: 457.0 ([{.sup.35Cl, .sup.35Cl}M+H].sup.+), ESI pos.

Example 63

(4S)-7,8-dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(91) ##STR00028##

a) (3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione

(92) In analogy to experiment of example 30 a, (3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (building block 0) was converted into the title compound (2.56 g, 67%) which was obtained as a light yellow solid. MS: 354.0 ([{.sup.35Cl, .sup.35Cl}M+H].sup.+), ESI pos.

b) (4S)-7,8-dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(93) In analogy to experiment of example 30 b, (3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted after chiral purification into the (+)-enantiopure (S)-title compound (8.8 mg, 2%) which was obtained as a white solid. MS: 440.1 ([{.sup.35Cl, .sup.35Cl}M+H].sup.+), ESI pos.

Example 64

(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one

(94) ##STR00029##

a) (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone

(95) To a solution of (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione (400 mg, 1.08 mmol) in tetrahydrofuran (8.7 mL) was added at room temperature hydrazine monohydrate (109 mg, 104 μl, 2.15 mmol). The mixture was stirred at room temperature for 2 h under argon. The suspension was concentrated in vacuo to give a light yellow solid that was treated with methyl tert-butyl ether (2 mL) and diluted with pentane (4 mL). The mixture was scratched to give a suspension that was stirred for 10 min. The solid was filtered, washed with pentane (2×3 mL) and dried in high vacuo to afford the title compound (300 mg, 75%) which was obtained as a yellow solid. MS: 369.1 ([{.sup.35Cl, .sup.35Cl}M+H].sup.+), ESI pos.

b) (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one

(96) To a solution of (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone (250 mg, 0.68 mmol) in tetrahydrofuran (6 mL) was added at room temperature 1,1′-carbonyldiimidazole (132 mg, 0.81 mmol). The reaction mixture was stirred at 70° C. for 5 h, then concentrated in vacuo. The residue was purified by SFC (Chiralcel OJ-3, 0.05% diethylamine in methanol, 5 to 40%) to give the (−)-enantiopure (S)-title compound (141.2 mg, 53%) which was obtained as a white solid. MS: 395.1 ({.sup.35Cl, .sup.35Cl}[M+H].sup.+), ESI pos.

Example 66

(4S)-7,8-dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(97) ##STR00030##

(98) In analogy to experiment of example 30 b, (3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using pyrimidine-4-carbohydrazide was converted after chiral purification into the (+)-enantiopure (S)-title compound (17 mg, 3%) which was obtained as a white solid. MS: 440.1 ([{.sup.35Cl, .sup.35Cl}M+H].sup.+), ESI pos.

Example 67

(4S)-7,8-dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(99) ##STR00031##

(100) In analogy to experiment of example 30 b, (3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using 1-methylpyrazole-4-carbohydrazide was converted after chiral purification into the (+)-enantiopure (S)-title compound (86 mg, 46%) which was obtained as a white solid. MS: 442.2 ([{.sup.35Cl, .sup.35Cl}M+H].sup.+), ESI pos.

Example 68

(4S)-7,8-dichloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(101) ##STR00032##

(102) In analogy to experiment of example 30 b, (3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using cyclopropanecarbohydrazide was converted after chiral purification into the (+)-enantiopure (S)-title compound (123 mg, 21%) which was obtained as a white solid. MS: 402.1 ([{.sup.35Cl, .sup.35Cl}M+H].sup.+), ESI pos.

Example 73

(4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(pyridazin-3-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

(103) ##STR00033##

a) (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione

(104) In analogy to experiment of example 30 a, (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (building block Q) was converted into the title compound (2.72 g, 77%) which was obtained as a yellow powder. MS: 415.1 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 417.0 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

b) (4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(105) In analogy to experiment of example 30 b, (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using pyridazine-3-carbohydrazide was converted after chiral purification into the (−)-enantiopure (S)-title compound (24 mg, 20%) which was obtained as a white solid. MS: 501.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 503.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 74

(4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(106) ##STR00034##

(107) In analogy to experiment of example 30 b, (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using pyrimidine-4-carbohydrazide was converted after chiral purification into the (−)-enantiopure (S)-title compound (13 mg, 11%) which was obtained as a white solid. MS: 501.1 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 503.0 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 75

(4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(108) ##STR00035##

(109) In analogy to experiment of example 30 b, (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using acetohydrazide was converted after chiral purification into the (−)-enantiopure (S)-title compound (36 mg, 23%) which was obtained as a white solid. MS: 437.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 439.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 76

(4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(110) ##STR00036##

(111) In analogy to experiment of example 30 b, (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using 1-methylpyrazole-4-carbohydrazide was converted after chiral purification into the (−)-enantiopure (S)-title compound (13 mg, 11%) which was obtained a white solid. MS: 503.1 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 505.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 80

(4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(112) ##STR00037##

(113) In analogy to experiment of example 30 b, (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using acetohydrazide was converted after chiral purification into the (−)-enantiopure (S)-title compound (13 mg, 11%) which was obtained as a white solid. MS: 436.9 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 438.9 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 81

(4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(1-methylpyrazol-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(114) ##STR00038##

(115) In analogy to experiment of example 30 b, (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using 1-methylpyrazole-3-carbohydrazide was converted after chiral purification into the (−)-enantiopure (S)-title title compound (38 mg, 26%) which was obtained as a white solid. MS: 503.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 505.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 82

(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(116) ##STR00039##

(117) In analogy to experiment of example 30 b, (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using acetohydrazide was converted after chiral purification into the (−)-enantiopure (S)-title compound (62.3 mg, 19%) which was obtained as a white solid. MS: 393.0 ([{.sup.35Cl, .sup.35C}M+H].sup.+), ESI pos. Example 83 (4S)-8-bromo-7-chloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(118) ##STR00040##

a) (3S)-7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione

(119) In analogy to experiment of example 30 a, (3S)-7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one (building block R) was converted into the title compound (720 mg, 46%) which was obtained as a yellow solid. MS: 398.0 ([{.sup.79Br, .sup.35C}M+H].sup.+), 400.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

b) (4S)-8-bromo-7-chloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(120) In analogy to experiment of example 30 b, (3S)-7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using cyclopropanecarbohydrazide was converted after chiral purification into the (+)-enantiopure (S)-title compound (38 mg, 11%) which was obtained as a light yellow solid. MS: 446.1 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 448.0 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 84

(4S)-8-bromo-7-chloro-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(121) ##STR00041##

(122) In analogy to experiment of example 30 b, (3S)-7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using formohydrazide was converted after chiral purification into the (+)-enantiopure (S)-title compound (38 mg, 12%) which was obtained as a light yellow solid MS: 406.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 408.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 85

(4S)-8-bromo-7-chloro-6-(3-fluoro-2-pyridyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(123) ##STR00042##

(124) In analogy to experiment of example 30 b, (3S)-7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using acetohydrazide was converted after chiral purification into the (+)-enantiopure (S)-title compound (31 mg, 8%) which was obtained as a white solid MS: 420.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 422.0 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 86

(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyridazin-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(125) ##STR00043##

a) 6-methylpyridazine-3-carbohydrazide

(126) A solution of ethyl 6-methylpyridazine-3-carboxylate (3.71 g, 22.3 mmol) in methanol (40 mL) was heated to 60° C. After 10 min, hydrazine-monohydrate (1.62 mL, 33.5 mmol) was carefully added and the reaction mixture was allowed to cool down to room temperature. Following up the addition of diethyl ether (60 mL), the reaction mixture was cooled down to 0° C. After 2 hours, the resulting suspension was filtered through a sintered funnel. The collected solid was washed with diethyl ether and dried under high vacuum to afford the title compound (1.4 g, 41%) which was obtained as an off-white powder. MS: 153.1 ([M+H].sup.+), ESI pos.

b) (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyridazin-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(127) In analogy to experiment of example 30 b, (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using 6-methylpyridazine-3-carbohydrazide was converted after chiral purification into the (−)-enantiopure (S)-title compound (52.6 mg, 44%) which was obtained as a white solid. MS: 471.1 ([{.sup.35Cl, .sup.35Cl}M+H].sup.+), ESI pos.

Example 87

5-[(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]-3-methyl-isoxazole

(128) ##STR00044##

a) 3-methyl-1,2-didehydroisoxazole-5-carbohydrazide

(129) In analogy to experiment of example 86 a, methyl 3-methyl-1,2-didehydroisoxazole-5-carboxylate was converted into the title compound (800 mg, 74%) which was obtained as a white solid. MS: 142.1 ([M+H].sup.+), ESI pos.

b) 5-[(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]-3-methyl-isoxazole

(130) In analogy to experiment of example 30 b, (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using 3-methyl-1,2-didehydroisoxazole-5-carbohydrazide was converted after chiral purification into the (−)-enantiopure (5)-title compound (54.1 mg, 31%) which was obtained as a white solid. MS: 460.1 ([{.sup.35Cl, .sup.35Cl}M+H].sup.+), ESI pos.

Example 88

(4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyridazin-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(131) ##STR00045##

(132) In analogy to experiment of example 30 b, (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using 6-methylpyridazine-3-carbohydrazide was converted after chiral purification into the (−)-enantiopure (S)-title compound (30 mg, 24%) which was obtained as a white solid MS: 515.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 517.0 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 89

(4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one

(133) ##STR00046##

a) (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone

(134) In analogy to experiment of example 64 a, (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione was converted into the title compound (40 mg, 20%) which was obtained as a powder. MS: 413.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 415.0 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

b) (4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one

(135) In analogy to experiment of example 64 b, (3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone was converted after chiral purification into the (−)-enantiopure (S)-title compound (12 mg, 28%) which was obtained as a white solid. MS: 439.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 441.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 92

(4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(136) ##STR00047##

a) (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one

(137) A solution of (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one (building block S, 500 mg, 1.12 mmol), iodocopper (426 mg, 2.24 mmol), hexamethylphosphoramide (2.5 mL, 1.12 mmol) and methyl 2,2-difluoro-2-fluorosulfonyl-acetate (645 mg, 3.36 mmol) in N,N-dimethylformamide (5 mL) was stirred at 70° C. for 16 h. Methyl 2,2-difluoro-2-fluorosulfonyl-acetate (430 mg, 2.24 mmol) and iodocopper (213 mg, 1.12 mmol) were added and the reaction mixture stirred at 70° C. for additional 4 h. The mixture was diluted with ethyl acetate (150 mL), washed with saturated aqueous ammonium chloride (80 mL) and the organic layer was filtered through a sintered funnel. The filtrate was washed with water (50 mL) and brine (50 mL), dried over sodium sulfate and concentrated in vacuo. The crude was purified by flash column chromatography (silica, petroleum ether/ethyl acetate, 20:1 to 1:1) to afford the title compound (550 mg, 127%) which was obtained as a dark red oil. MS: 389.0 ([M+H].sup.+), ESI pos.

b) (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione

(138) In analogy to experiment of example 30 a, (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-one was converted into the title compound (400 mg, 77%) which was obtained as a yellow solid. MS: 405.0 ([M+H].sup.+), ESI pos.

c) (4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(139) In analogy to experiment of example 30 b, (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione using acetohydrazide was converted after chiral purification into the (−)-enantiopure (S)-title compound (63.5 mg, 32%) which was obtained as a white solid. MS: 427.1 ([M+H].sup.+), ESI pos.

Example 93

(4S)-7-chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(140) ##STR00048##

a) (4S)-7-chloro-6-(2,6-difluorophenyl)-8-(1-ethoxyvinyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(141) To a suspension of (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (example 75, 210.0 mg, 0.480 mmol) and tributyl(1-ethoxyvinyl)tin (346.57 mg, 0.960 mmol) in N,N-dimethylformamide (2.1 mL) was added tetrakis(triphenylphosphine)palladium(0) (56.42 mg, 0.050 mmol). The reaction mixture was stirred at 80° C. for 1 h. The mixture was diluted with dichloromethane (2×20 mL), washed with water (20 mL) and brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica, petroleum ether/ethyl acetate 10:1, dichloromethane/methanol 80:1) to afford the title compound (300 mg, 98%) which was obtained as a colorless oil. MS: 429.1 ([M+H].sup.+), ESI pos.

b) 1-[(4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl]ethanone

(142) To a solution of (4S)-7-chloro-6-(2,6-difluorophenyl)-8-(1-ethoxyvinyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine_(280 mg, 0.650 mmol) in 1,4-dioxane (7 mL) was added aqueous hydrochloric acid (2.0 M, 1.62 mL, 3.23 mmol). The mixture was stirred at room temperature for 0.5 h, before being diluted with dichloromethane (100 mL). The organic layer was washed with water (3×10 mL), aqueous sodium bicarbonate (3×50 mL) and brine (50 mL), then dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (Boston Prime C18, 0.1% trifluoroacetic acid in water/acetonitrile) and lyophilized to afford the title compound (220 mg, 84%) which was obtained as a light yellow solid. MS: 401.1 ([M+H].sup.+), ESI pos.

c) (4S)-7-chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(143) To a solution 1-[(4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl]ethanone (100 mg, 0.250 mmol) in dichloroethane (2 mL) was added diethylaminosulfur trifluoride (120.6 mg, 0.750 mmol) at 0° C. The mixture was stirred at room temperature for 24 h, before being poured into saturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with dichloromethane (2×50 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Synergi C18, 0.1% trifluoroacetic acid in water/acetonitrile) to afford the (−)-enantiopure (S)-title compound (20.1 mg, 18%) which was obtained as a white solid. MS: 423.0 ([M+H].sup.+), ESI pos.

Example 94

(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyrimidin-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(144) ##STR00049##

(145) In analogy to experiment of example 30 b, (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using 6-methylpyrimidine-4-carbohydrazide was converted after chiral purification into the (−)-enantiopure (S)-title compound (70.0 mg, 35%) which was obtained as a white solid. MS: 471.2 ([{.sup.35Cl, .sup.35Cl}M+H]+), ESI pos.

Example 95

(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(2-methylpyrimidin-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(146) ##STR00050##

(147) In analogy to experiment of example 30 b, (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using 2-methylpyrimidine-4-carbohydrazide was converted after chiral purification into the (−)-enantiopure (S)-title compound (12.0 mg, 20%) which was obtained as a white solid. MS: 471.2 ([{.sup.35Cl, .sup.35C}M+H].sup.+), ESI pos.

Example 96

(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-1-(2,6-dimethylpyrimidin-4-yl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(148) ##STR00051##

(149) In analogy to experiment of example 30 b, (3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione using 2,6-dimethylpyrimidine-4-carbohydrazide was converted after chiral purification into the (−)-enantiopure (S)-title compound (66.8 mg, 44%) which was obtained as a white solid. MS: 485.1 ([{.sup.35Cl, .sup.35C}M+H]+), ESI pos.

Example 97

(4S)-7-chloro-6-(2,6-difluorophenyl)-1,4,8-trimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(150) ##STR00052##

(151) A mixture of (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (300 mg, 0.690 mmol), tetrakis (triphenylphosphine) palladium (0) (79.2 mg, 0.070 mmol), trimethylaluminum (2.0 M in toluene, 0.51 mL, 1.03 mmol) in N,N-dimethylformamide (6 mL) was heated to 70° C. After 16 h, the mixture was diluted with dichloromethane (30 mL). The organic layer was washed with water (20 mL), brine (30 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (Boston Prime, 0.1% trifluoroacetic acid in water/acetonitrile) and lyophilized to afford the (−)-enantiopure (S)-title compound (27.3 mg, 58%) which was obtained as a white solid. MS: 373.2 ([M+H].sup.+), ESI pos.

Example 98

(4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-ethyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(152) ##STR00053##

a) (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepine-2-thione

(153) In analogy to experiment of example 30 a, (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepin-2-one (building block T) was converted into the title compound (600 mg, 92%) which was obtained as a yellow solid. MS: 429.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 431.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

b) (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone

(154) A solution of (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepine-2-thione (500 mg, 1.16 mmol) and hydrazine hydrate (117 mg, 2.33 mmol) in tetrahydrofuran (5 mL) was cooled to 15° C. and stirred for 1 h. The mixture was concentrated in vacuo to afford the title compound (450 mg, 90%) as a light green foam. MS: 427.2 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 429.3 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

c) (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-ethyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(155) A solution of (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone (450 mg, 1.05 mmol) and triethyl orthoacetate (854 mg, 5.26 mmol) in toluene (5 mL) was heated to 120° C. After 1 h, the reaction mixture was concentrated in vacuo. The residue was purified directly by flash column chromatography (dichloromethane/methanol 20:1) followed by chiral purification to afford the (−)-enantiopure (S)-title compound (400 mg, 82%) as a light yellow foam. MS: 451.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 453.0 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 99

(4S)-7-chloro-8-(difluoromethyl)-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(156) ##STR00054##

a) (4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-8-vinyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(157) To a solution of (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (3.0 g, 6.85 mmol) in ethanol (70 mL) was added potassium vinyltrifluoroborate (1.85 g, 1.37 mmol), triethylamine (2.08 g, 20.56 mmol), [1, 1′-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (0.5 g, 0.690 mmol). The reaction mixture was heated to 80° C. After 16 h, water (100 mL) was added and the reaction mixture was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate/ethanol 20:3:1 to 8:3:1) to afford the title compound (2.8 g, 88%) which was obtained as a brown solid. MS: 385.1 ([M+H].sup.+), ESI pos.

b) (4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-8-carbaldehyde

(158) To a solution of (4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-8-vinyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (2.8 g, 7.28 mmol) in acetone (56 mL) and water (14 mL) was added osmium tetroxide (184.99 mg, 0.730 mmol). After 10 min stirring at room temperature, sodium periodate (3.1 g, 14.5 mmol) was added and the mixture was stirred for further 1 h at room temperature. The reaction mixture was diluted with water (10 mL) and ethyl acetate (100 mL). The organic layer was washed with brine (2×50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, dichloromethane/methanol 200:1 to 60:1) to afford the title compound (1.8 g, 47%) which was obtained as a yellow solid. MS: 387.1 ([M+H].sup.+), ESI pos.

c) (4S)-7-chloro-8-(difluoromethyl)-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(159) To a solution of (4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-8-carbaldehyde (1.8 g, 4.65 mmol) in dichloroethane (37.0 mL) was added diethylaminosulfur trifluoride (2.25 g, 14.0 mmol) at 0° C. Upon addition, the reaction mixture was warmed up to room temperature and stirred for further 2 h. The reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate (10 mL), then extracted with dichloromethane (2×30 mL). The combined organic extracts were washed with brine (2×50 mL), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Boston Prime C18, 0.1% trifluoroacetic acid in water/acetonitrile) and lyophilized to afford the (−)-enantiopure (S)-title compound (359 mg, 50%) which was obtained as a white solid. MS: 409.1 ([M+H].sup.+), ESI pos.

Example 100

(4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(160) ##STR00055##

a) (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione

(161) In analogy to experiment of example 30 a, (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl)-1,3-dihydro-1,4-benzodiazepin-2-one (building block U) was converted into the title compound (1.2 g, 76%) which was obtained as a yellow solid. MS: 445.0 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 447.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

b) (3R)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl)-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone

(162) In analogy to experiment of example 98 b, (3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione was converted into the title compound (1.1 g, 96%) which was obtained as a yellow solid. MS: 443.1 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 445.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

c) (4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(163) In analogy to experiment of example 98 c, (3R)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl)-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone was converted after chiral purification into the (−)-enantiopure (R)-title compound (68 mg, 6%) which was obtained as a white solid. MS: 467.2 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 469.1 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 101

[(4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]methanol

(164) ##STR00056##

(165) To a stirred suspension of (4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (230.0 mg, 0.490 mmol) and sodium iodide (147.43 mg, 0.980 mmol) in dichloromethane (3 mL) was added at −30° C. a solution of boron tribromide (308.0 mg, 1.23 mmol) in dichloromethane (0.5 mL). The reaction mixture was warmed up to room temperature and stirred for further 1 h, before being concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex luna, 0.1% trifluoroacetic acid in water/acetonitrile) then SFC (Daicel Chiralpak AD-H, 0.1% ammonia in methanol) to afford the (−)-enantiopure (R)-title compound (71 mg, 47%) as a white solid. MS: 453.2 ([{.sup.79Br, .sup.35Cl}M+H].sup.+), 455.2 ([{.sup.81Br, .sup.35Cl or .sup.79Br, .sup.37Cl}M+H].sup.+), ESI pos.

Example 102

(4S)-7-chloro-6-(2,6-difluorophenyl)-8-iodo-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(166) ##STR00057##

(167) To a mixture of (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (100 mg, 0.228 mmol), rac-trans-N1,N2-dimethylcyclohexane-1,2-diamine (35.3 μL, 0.228 mmol), sodium iodide (342 mg, 2.28 mmol) and copper(I) iodide (21.8 mg, 114 μmol) was added 1,4-dioxane (10 mL) under Argon. The resulting suspension was heated to 115° C. for 6 days. A further amount of sodium iodide (685 mg, 4.57 mmol) and copper(I) iodide (218 mg, 1.14 mmol) were added and the reaction mixture was stirred for further 2 days. The mixture was diluted with ethyl acetate and the organic layer was washed twice with aqueous ammonia, brine, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash column chromatography (silica, methanol in dichloromethane 0-15%), followed by chiral HPLC (Chiracel OD; eluent: 20% (ammonium acetate 0.1 mol in ethanol) in heptane) to afford the (−)-enantiopure (S)-title compound (41.2 mg, 37%) as a white solid. MS: 485.0 ([M+H].sup.+), ESI pos.

Example 103

[(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methanol

(168) ##STR00058##

a) [(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methoxy-triisopropyl-silane

(169) In analogy to experiment of example 30 b, (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione using 2-triisopropylsilyloxyacetohydrazide was converted into the title compound (300 mg, 33%) which was obtained as a light yellow oil. MS: 599.2 ([M+H].sup.+), ESI pos.

b) [(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methanol

(170) To a solution of [(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methoxy-triisopropyl-silane (200.0 mg, 0.270 mmol) in tetrahydrofuran (4 mL) was slowly added TBAF (1.0 M in tetrahydrofuran, 0.81 mL, 0.810 mmol). The mixture was stirred at room temperature for 1 h, before being concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane/methanol 50:1 to 20:1), followed by preparative HPLC (UniSil 3-100 C18 Uitra, 0.225% trifluoroacetic acid in water/acetonitrile) and SFC separation (Daicel Chiralcel OJ, 0.1% ammonia in ethanol) to afford the (−)-enantiopure (S)-title compound (13.6 mg, 10%) as a white solid. MS: 443.0 ([M+H].sup.+), ESI pos.

Example 105

(4R)-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(171) ##STR00059##

(172) To an oven-dried vial equipped with a magnetic stir bar and a Teflon septum was added (4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (10 mg, 21.4 □mol), sodium carbonate (9.06 mg, 85.5 □mol), CuBr.sub.2.Math.2LiBr (4.28 μmol), Mes-Umemoto reagent (22 mg, 42.8 □mol), Ir[dFMeppy]2-(4,4′-dCF.sub.3bpy)PF.sub.6 (56 μg, 0.0535 μmol) and (Me.sub.3Si.sub.3)SiOH (8.5 mg, 32.1 μmol). The vial was then degassed by alternative evacuation and back filling with nitrogen, then degassed acetone (0.2 mL) was added via syringe addition. The reaction mixture was stirred at room temperature for 16 h under irradiation of a blue LED (Kessil lamp 40 W, 420 nm). The vial was opened and the reaction mixture was filtered directly through a plug of celite. The filter cake was rinsed with ethyl acetate (2.0 mL) and the filtrate concentrated in vacuo. The residue was dissolved in ethyl acetate (20 mL) and washed with water and brine (3×15 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (Gemini NX5Y, 0.1% formic acid in water/acetonitrile) to afford the (−)-enantiopure (R)-title compound (3 mg, 30%) as a white solid. MS: 457.2 ([M+H]+), ESI pos.

Example 106

[(4R)-7-chloro-6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]methanol

(173) ##STR00060##

(174) In analogy to experiment of example 105, [(4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]methanol was converted into the (−)-enantiopure (R)-title compound (9 mg, 31%) which was obtained as a white lyophilized powder. MS: 443.1 ([M+H].sup.+), ESI pos.

Example 107

(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(175) ##STR00061##

(176) In analogy to experiment of example 105, (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted into the (−)-enantiopure (S)-title compound (1 mg, 10%) which was obtained as a white solid. MS: 413.2 ([M+H]H), ESI pos.

Example 108

(4S)-7-chloro-6-(2,6-difluorophenyl)-1-ethyl-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(177) ##STR00062##

(178) In analogy to experiment of example 30 b, (3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione using propanehydrazide was converted after chiral purification into the (−)-enantiopure (S)-title compound (16.4 mg, 13%) which was obtained as a white solid. MS: 444.1 ([M+H].sup.+), ESI pos.

Example 109

(4S)-7-chloro-6-(2,6-difluorophenyl)-8-ethyl-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(179) ##STR00063##

(180) To a solution of (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (120 mg, 0.274 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)CH.sub.2Cl.sub.2 (4.5 mg, 5.5 μmop in dry tetrahydrofuran (1.2 mL) at 0° C. was added dropwise diethylzinc (1.0 M in heptane, 0.823 mL, 0.823 mmol). The reaction was allowed to warm to room temperature, before being heated to 55° C. for 15 h. The reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (Gemini NX, 0.1% triethylamine in water/methanol), followed by chiral HPLC (Reprosil Chiral NR, 0.01 M ammonium acetate in ethanol, 30%) to afford the (−)-enantiopure (S)-title compound (31.7 mg, 30%) as a white powder. MS: 387.3 ([M+H].sup.+), ESI pos.

Reference Compounds

(181) RE-A

8-bromo-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(182) ##STR00064##

a) N-[2-(2,6-difluorobenzoyl)phenyl]acetamide

(183) In analogy to experiment of building block A b, 2-methyl-3,1-benzoxazin-4-one (CAS #525-76-8) was converted into the title compound (40 g, 80%) which was obtained as a light yellow solid. MS: 276.2 ([M+H].sup.+), ESI pos.

b) (2-aminophenyl)-(2,6-difluorophenyl)methanone

(184) In analogy to experiment of building block A c, N-[2-(2,6-difluorobenzoyl)phenyl]acetamide was converted into the title compound (19.5 g, 75%) which was obtained as a yellow solid. MS: 234.1 ([M+H].sup.+), ESI pos.

c) (2-amino-5-bromo-phenyl)-(2,6-difluorophenyl)methanone

(185) To a solution of (2-aminophenyl)-(2,6-difluorophenyl)methanone (5.00 g, 21.4 mmol) in dichloromethane (50 mL) was added portionwise N-bromosuccinimide (4.02 g, 22.51 mmol) at −15° C. The reaction mixture was stirred at −15° C. for 1 h, till complete consumption of starting material (as judged by LCMS analysis). The mixture was concentrated under reduced pressure and the resulting residue purified by preparative HPLC (Shim-pack C18, 0.225% trifluoroacetic acid in water/acetonitrile). The combined fractions were diluted with saturate aqueous sodium bicarbonate and extracted with ethyl acetate (3×200 mL). The organic phase was washed with brine (2×100 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo to afford the title compound (4.44 g, 66%) as a yellow solid. MS: 311.9 ([{.sup.79Br}M+H].sup.+), 314.0 ([{.sup.81Br}M+H].sup.+), ESI pos.

d) 7-bromo-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one

(186) In analogy to experiment of building block A e, (2-amino-5-bromo-phenyl)-(2,6-difluorophenyl)methanone was converted into the title compound (300 mg, 13%) which was obtained as a yellow solid. MS: 351.0 ([{.sup.79Br}M+H].sup.+), 353.0 ([{.sup.81Br}M+H].sup.+), ESI pos.

e) 7-bromo-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione

(187) In analogy to experiment of example 30 a, 7-bromo-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one was converted into the title compound (310 mg, 92%) which was obtained as a yellow solid. The crude was used as such in the following step without further characterization.

f) 8-bromo-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(188) In analogy to experiment of example 30 b, 7-bromo-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione using acetohydrazide was converted into the title compound (5.1 mg, 4%) which was obtained as a white solid. MS: 389.0 ([{.sup.79Br}M+H].sup.+), 391.0 ([{.sup.81Br}M+H].sup.+), ESI pos.

(189) RE-B

6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(190) ##STR00065##

a) (2-amino-5-iodo-phenyl)-(2,6-difluorophenyl)methanone

(191) To a solution of (2-aminophenyl)-(2,6-difluorophenyl)methanone (1.6 g, 6.86 mmol) in DMF (15 mL) was added portionwise N-iodosuccinimide (1.62 g, 7.2 mmol). The reaction mixture was stirred at 20° C. for 16 h, before being diluted with water (20 mL). The mixture was extracted with ethyl acetate (3×20 mL), then the combined organic extracts were washed with brine (2×10 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate, 10:1 to 5:1) to afford the title compound (2.0 g, 81%) as a yellow solid. MS: 360.0 ([M+H].sup.+), ESI pos.

b) 5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one

(192) In analogy to experiment of building block A e, (2-amino-5-iodo-phenyl)-(2,6-difluorophenyl)methanone was converted into the title compound (650 mg, 12%) which was obtained as a yellow solid. MS: 399.0 ([M+H].sup.+), ESI pos.

c) 5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepine-2-thione

(193) In analogy to experiment of example 30 a, 5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one was converted into the title compound (200 mg, 82%) which was obtained as a yellow solid. MS: 414.9 ([M+H].sup.+), ESI pos.

d) 5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone

(194) In analogy to experiment of example 64 a, 5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepine-2-thione was converted into the title compound (220 mg, 98%) which was obtained as a yellow solid. MS: 413.0 ([M+H].sup.+), ESI pos.

e) 6-(2,6-difluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(195) In analogy to experiment of example 98 c, 5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one hydrazone was converted into the title compound (150 mg, 64%) which was obtained as a yellow solid. MS: 437.0 ([M+H].sup.+), ESI pos.

f) 6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(196) In analogy to experiment of example 92 a, 6-(2,6-difluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted into the title compound (5 mg, 6%) which was obtained as a white solid. MS: 379.0 ([M+H].sup.+), ESI pos.

(197) RE-C

6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(198) ##STR00066##

(199) To a stirred solution of 8-bromo-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (30 mg, 0.08 mmol) in methanol (0.5 mL) was added 10 wt. % Pd/C (2.5 mg, 2.4 μmop and the resulting black suspension was purged by evacuation and then back filled with a stream of hydrogen (balloon) for three times. The mixture was stirred for 16 hours at room temperature under hydrogen atmosphere then filtered through a pad of dicalite. The filter cake was rinsed with methanol and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex Gemini-NX C18, 0.1% trifluoroacetic acid in water/acetonitrile) followed by preparative TLC (silica, dichloromethane/methanol, 20:1) to obtain the title compound (5 mg, 20%) as a white solid. MS: 276.2 ([M+H].sup.+), ESI pos.

(200) RE-D

(4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(201) ##STR00067##

(202) In analogy to experiment of reference compound RE-C, (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine was converted into the title compound (2 mg, 15%) which was obtained as a white solid. MS: 359.1 ([M+H].sup.+), ESI pos.