Tetracyclic compound

Compound A2

7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one

7-Methoxy-3,4-dihydro-1H-naphthalen-2-one (Compound A1, 209 g, 1.18 mol), tetrabutylammonium hydrogen sulfate (40 g, 0.118 mol) and methyl iodide (162 g, 2.60 mol) were suspended in THF (500 ml) at room temperature. Under stirring, the mixture was added with 50% aqueous solution of potassium hydroxide (400 g) over 5 min. Reflux occurred as the inner temperature rapidly increases. Once the inner temperature stopped to increase, stirring was continued for 45 min. The reaction solution was diluted with distilled water (1 L) and extracted twice with CPME (1.5 L). The combined organic layer was washed (distilled water 1 L×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was recrystallized with MeOH (1 L) and distilled water (500 ml) to obtain the title compound as a colorless needle-like crystal (177 g, 73%).

1 H-NMR (400 MHz, CDCl 3 ) δ: 1. 43 (6H, s), 2. 65 (2H, t, 12 Hz), 3. 02 (2H, t, 12 Hz), 3. 79 (3H, s), 6. 74 (1H, m), 6. 87 (1H, m), 7. 24 (1H, m).

LCMS: m/z 205 [M+H] +

Compound A3-1

Compound A3-2

3-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole

1-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole

7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 66.2 g, 324 mmol) and 3-bromophenylhydrazine hydrochloric acid salt (71.0 g, 318 mmol) were dissolved in AcOH (350 ml) and refluxed under stirring for 6 hr. The reaction solvent was removed by distillation under reduced pressure to obtain the crude product as a mixture of the title compound A3-1 and A3-2.

Compound A4

3-Bromo-8-methoxy-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one

The crude product obtained from the above (i.e., mixture of A3-1 and A3-2) was dissolved in a mixture solvent of THF (450 ml) and distilled water (50 ml), added once with DDQ (115 g, 509 mmol), and then stirred at room temperature for 1 hr. The reaction mixture was diluted with CPME 3 L, and the organic layer was washed three times with 0.5 N aqueous solution of sodium hydroxide (1 L) and twice with distilled water (1 L) in order and dried over anhydrous sodium sulfate. The organic layer was concentrated to 500 ml under reduced pressure. The precipitated product was collected by filtration and washed with a small amount of CPME to obtain the title compound as a yellow crystal (48 g, 40%).

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1. 73 (6H, s), 3. 90 (3H, s), 7.06-7. 09 (1H, m), 7.32-7. 38 (2H, m), 7.65-7. 66 (1H, m), 8.09-8.17 (2H, m), 12. 32 (1H, br. s).

LCMS: m/z 370, 372 [M+H] +

Compound AA1

4-Methoxy-2-(3-trimethylsilanylprop-2-ynyl)-benzoic acid methyl ester

To the THF (16 ml) solution of 2-bromomethyl-4-methoxy-benzoic acid methyl ester (961 mg, 4.09 mmol), triphenylphosphine (107 mg, 0.1 eq.), cesium carbonate (1.87 g, 1.4 eq.), copper iodide (59 mg, 0.076 eq.) and tris(dibenzylideneacetone)dipalladium (86 mg, 0.023 eq.) were added, degassed, flushed with nitrogen gas, added with trimethylsilylacetylene (734 μl, 1.3 eq.), and then stirred overnight at 55° C. To the reaction solution, saturated aqueous solution of ammonium chloride was added followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (brown oily substance, 606 mg, 54%).

1 H-NMR (400 MHz, CDCl 3 ) δ: 7. 93 (1H, d, J=8.8 Hz), 7. 33 (1H, d, J=2.6 Hz), 6. 78 (1H, dd, J=8.8, 2.6 Hz), 4. 09 (2H, s), 3. 86 (3H, s), 3. 84 (3H, s), 0.14 (9H, s).

LCMS: m/z 277 [M+H] +

HPLC retention time: 3.30 min (analysis condition U)

Compound AA2

2-(1,1-Dimethyl-3-trimethylsilanylprop-2-ynyl)-4-methoxy-benzoic acid methyl ester

To the toluene (4 ml) solution of 4-methoxy-2-(3-trimethylsilanyl-prop-2-ynyl)-benzoic acid methyl ester (Compound AA1, 273 mg, 0.988 mmol), sodium bis(trimethylsilyl)amide (2.1 ml, 1.9 m solution, 4 eq.) and iodomethane (308 μl, 5 eq.) were added at −78° C. After allowing the reaction temperature to increase to the room temperature, the mixture was stirred for 2 hr. To the reaction solution, saturated aqueous solution of ammonium chloride was added followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (yellow oily substance, 226 mg, 75%).

1 H-NMR (400 MHz, CDCl 3 ) δ: 7. 45 (1. 0H, d, J=8.4 Hz), 7. 09 (1. 1H, d, J=2.6 Hz), 6. 75 (1H, m), 3. 84 (3H, s), 3. 82 (3H, s), 1.70 (6H, s), 0.14 (9H, s)

LCMS: m/z 305 [M+H] +

HPLC retention time: 3.38 min (analysis condition U)

Compound AA3

2-(1,1-Dimethylprop-2-ynyl)-4-methoxy-benzoic acid methyl ester

To the THF (18 ml) solution of 2-(1,1-dimethyl-3-trimethylsilanylprop-2-ynyl)-4-methoxy-benzoic acid methyl ester (Compound AA2, 912 mg, 3 mmol), tetrabutylammonium fluoride (2.061 g, 2.6 eq.) was added, and then stirred for 3 hr at room temperature. To the reaction solution, saturated aqueous solution of ammonium chloride was added followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (yellow oily substance, 524 mg, 75%).

1 H-NMR (400 MHz, CDCl 3 ) δ: 7. 44 (1H, d, J=8.4 Hz), 7. 05 (1H, d, J=2.3 Hz), 6. 76 (1H, dd, J=8.4, 2.3 Hz), 3. 84 (3H, s), 3. 82 (3H, s), 1.73 (6H, s)

LCMS: m/z 223 [M+H] +

HPLC retention time: 2.55 min (analysis condition U)

Compound AA4

2-[1-(6-Cyano-1-methanesulfonyl-1H-indol-2-yl)-1-methylethyl]-4-methoxy-benzoic acid methyl ester

To the DMF (2 ml) solution of 2-(1,1-dimethylprop-2-ynyl)-4-methoxy-benzoic acid methyl ester (Compound AA3, 134 mg, 0.577 mmol) and N-(2-bromo-5-cyanophenyl)methanesulfonamide (Compound AA5, 167 mg, 1.05 eq.), copper iodide (9 mg, 0.08 eq.) and TEA (129 μl, 1.6 eq.) were added, degassed and flushed with nitrogen gas, added with dichlorobis(triphenylphosphine) palladium (20 mg, 0.05 eq.), and then degassed and flushed again with nitrogen gas. After stirring for 2 hr at 90° C., the reaction solution was added with water, extracted with ethyl acetate. The organic layer was washed with an brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (white solid, 152 mg, 62%).

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8. 19 (1H, dd, J=0.6, 0.6 Hz), 7. 84 (1H, dd, J=8. 0, 0. 6 Hz), 7. 67 (1H, dd, J=8. 0, 1. 3 Hz), 7. 13 (1H, d, J=8. 4 Hz), 6. 99 (1H, s), 6. 96 (1H, br. s), 6. 85 (1H, dd, J=8.4, 2.5 Hz), 3. 78 (3H, s), 3. 12 (3H, s), 3. 09 (3H, br. s), 1. 89 (6H, s).

LCMS: m/z 427 [M+H] +

HPLC retention time: 2.77 min (analysis condition U)

Compound AA1

N-(2-Bromo-5-cyanophenyl)methanesulfonamide

To a mixture of 3-amino-4-bromo-benzonitrile (1.98 g, 10 mmol), TEA (5.06 g, 50 mmol), and methylene chloride (50 ml), mesyl chloride (2.71 ml, 35 mmol) was added at 0° C. and the mixture was stirred at room temperature for 30 min. Water was added to the reaction solution, which was then extracted with dichloromethane. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were added with tetrahydrofuran (100 ml), water (400 μl) and sodium hydride (540 mg, 15.5 mmol), and stirred at room temperature for 16 hr. To the reaction solution, saturated aqueous solution of ammonium chloride (200 ml) was added followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.48 g, 90%).

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 9. 82 (1H, s), 7. 87 (1H, d, J=4 Hz), 7. 75 (1H, d, J=8 Hz), 7. 70 (1H, dd, J=8 Hz, 4 Hz), 3. 14 (3H, s)

HPLC retention time: 1.63 min (analysis condition U)

Compound AA6

2-(1-Hydroxy-1-methylethyl)-1H-indole-6-carbonitrile

To N-(2-bromo-5-cyanophenyl)methanesulfonamide (Compound AA5, 230 mg, 1 mmol), 3-methyl-2-butyn-3-ol (0.15 ml, 1.5 mmol), X-Phos (72 mg, 15% mol), PdCl 2 (CH 3 CN) 2 (13 mg, 5% mol) and cesium carbonate (390 mg, 2 mmol), DMA (2 ml) was added, and the mixture was stirred at 100° C. for 3 hr. Water and 5 N hydrochloric acid solution were added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (130 mg, 75%).

1 H-NMR (400 MHz, CDCl 3 ) δ: 8. 76 (1H, s), 7. 68 (1H, s), 7. 60 (1H, d, J=8 Hz), 7. 32 (1H, dd, J=8 Hz, 4 Hz), 6. 37 (1H, m), 1. 93 (1H, s), 1. 70 (6H, s)

LCMS: m/z 201 [M+H] +

HPLC retention time: 2.12 min (analysis condition U)

Compound A5-1

3-Bromo-8-hydroxy-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A6, the title compound was synthesized from Compound A4.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 30 (1H, s), 10. 21 (1H, s), 8.06-8. 11 (1H, m), 8.01-8. 05 (1H, m), 7.62-7. 66 (1H, m), 7.32-7. 37 (1H, m), 7.08-7. 12 (1H, m), 6.84-6. 90 (1H, m), 1. 69 (6H, s).

LCMS: m/z 356, 358 [M+H] +

HPLC retention time: 2.30 min (analysis condition U)

Compound A5-2

8-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

(Method 1) 3-Bromo-8-methoxy-6,6-dimethyl-5,6-dihydrobenzo[b]carbazol-11-one (Compound A4, 10.45 g, 28.2 mmol) and copper (I) cyanide (5.0 g, 50.2 mmol) were dissolved in NMP (100 ml), followed by stirring at 170° C. for 17 hr. The reaction mixture was suspended in ethyl acetate (500 mL) and distilled water (200 mL). The insoluble matters were removed by Celite filtration and washed twice with ethyl acetate (300 mL×2). The organic layer was washed once with an aqueous solution of disodium EDTA (200 mL) and twice with saturated brine (200 mL) in order, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to yield a product, which was suspended and washed with a small amount of CPME to obtain the title compound as a colorless crystal (6.58 g, 73%).

(Method 2) To the THF (5.6 ml) solution of 2-[1-(6-cyano-1-methanesulfonyl-1H-indol-2-yl)-1-methylethyl]-4-methoxy-benzoic acid methyl ester (Compound AA4, 138 mg, 0.324 mmol), tetrabutylammonium fluoride (514 mg, 6 eq.) was added, and the mixture was stirred at room temperature overnight. Thereafter, 2 M aqueous solution of sodium hydroxide (5.6 ml) was added to the mixture, which was then stirred for 4 hr, added with 1 M HCl, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were dissolved in ethyl acetate (10 ml) and added with e 4 M HCl and ethyl acetate solution (10 ml) followed by stirring at room temperature for 30 min. The residues obtained after concentration of the reaction solution under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (89.2 mg, 62%).

(Method 3) To nitrobenzene (5 ml) and aluminum chloride (400 mg, 3 mmol), 4-methoxybenzoyl chloride (400 mg, 2.3 mmol) was added. After stirring for 30 min at room temperature, 2-(1-hydroxy-1-methyl-ethyl)-1H-indole-6-carbonitrile (Compound AA6, 200 mg, 1 mmol) was added followed by stirring at room temperature for 3 hr. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (127 mg, 40%).

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1. 71 (6H, s), 3. 89 (3H, s), 7.07-7. 09 (1H, m), 7. 34 (1H, s), 7.58-7. 60 (1H, m), 7. 99 (1H, s), 8.14-8. 16 (1H, m), 8.30-8. 32 (1H, m), 12. 32 (1H, br. s),

LCMS: m/z 317 [M+H] +

HPLC retention time: 2.56 min (analysis condition U)

Compound A6

8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

8-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A5-2, 6.58 g, 20.8 mmol) was dissolved in pyridine hydrochloric acid salt (25.0 g), and stirred at 170° C. for 13 hr. The reaction mixture was partitioned in ethyl acetate (400 mL) and distilled water (400 mL), and the aqueous layer was extracted one more time with ethyl acetate (400 mL). The combined organic layer was washed twice with distilled water (100 mL) and once with saturated brine (100 mL) in order, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to yield a product, which was suspended and washed with a small amount of CPME to obtain the title compound as a colorless crystal (5.91 g, 93%).

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1. 73 (6H, s), 6.87-6. 90 (1H, m), 7. 11 (1H, s), 7.57-7. 59 (1H, m), 7. 97 (1H, s), 8.04-8. 06 (1H, m), 8.29-8. 31 (1H, m), 10. 27 (1H, s), 12. 66 (1H, br. s),

LCMS: m/z 303 [M+H] +

Compound A7-1

4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-piperidine-1-carboxylic acid tert-butyl ester

8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A6, 30 mg, 0.099 mmol) was dissolved in THF (1 mL), added with 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (40 mg, 2 eq.), triphenylphosphine (52 mg, 2 eq.), and diisopropyl azodicarboxlyate (43 μL, 2 eq.) in order, and stirred at room temperature for 4 hr. The reaction solution was poured to water, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (37 mg, 76%).

1 H-NMR (400 MHz, CDCl 3 ) δ: 9. 44 (1H, s), 8. 77 (1H, d, J=7.8 Hz), 8. 62 (1H, d, J=8.2 Hz), 8. 00 (1H, s), 7. 81 (1H, d, J=8.2 Hz), 7. 34 (1H, s), 7. 26 (1H, d, J=7.8 Hz), 4.85-4. 93 (1H, m), 3.96-4. 04 (2H, m), 3.60-3. 70 (2H, m), 2.19-2. 32 (2H, m), 1.89-2. 15 (8H, m), 1. 74 (9H, s)

LCMS: m/z 430 [M+H] +

HPLC retention time: 4.09 min (analysis condition W)

Compound A7-2

6,6-Dimethyl-11-oxo-8-[2-(2-oxo-imidazolidin-1-yl)-ethoxy]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 1-(2-hydroxy-ethyl)-imidazolidin-2-one.

LCMS: m/z 415 [M+H] +

HPLC retention time: 2.96 min (analysis condition W)

Compound A7-3

[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl]-carbamic acid tert-butyl ester

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and (2-hydroxy-ethyl)-carbamic acid tert-butyl ester.

LCMS: m/z 346 [M+H] +

HPLC retention time: 2.40 min (analysis condition W)

Compound A7-4

6,6-Dimethyl-8-(2-methylsulfanyl-ethoxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 2-methylthioethanol.

LCMS: m/z 451 [M+H] +

HPLC retention time: 4.23 min (analysis condition W)

Compound A7-5

6,6-Dimethyl-8-(2-methylsulfanyl-ethoxy)-5-(2-methylsulfanyl-ethyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

The title compound was obtained as a by-product of the synthesis of Compound A7-4.

LCMS: m/z 377 [M+H] +

HPLC retention time: 3.75 min (analysis condition W)

Compound A7-6

6,6-Dimethyl-11-oxo-8-(tetrahydro-pyran-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and tetrahydropyran-4-ol.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 72 (1H, br. s), 8. 32 (1H, d, 8. 5 Hz), 8. 15 (1H, d, 8. 5 Hz), 8. 01 (1H, s), 7. 61 (1H, d, 8. 5 Hz), 7. 38 (1H, s), 7. 15 (1H, d, 8. 5 Hz), 4.86-4. 81 (1H, m), 3.93-3. 88 (2H, m), 3.58-3. 52 (2H, m), 2.06-2. 00 (2H, m), 1. 85 (6H, s), 1.69-1. 60 (2H, m)

LCMS: m/z 387 [M+H] +

HPLC retention time: 3.47 min (analysis condition W)

Compound A7-7

6,6-Dimethyl-11-oxo-8-(pyridin-4-ylmethoxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and pyridin-4-yl-methanol.

LCMS: m/z 394 [M+H] +

HPLC retention time: 2.56 min (analysis condition W)

Compound A7-8

8-(2-Methoxyethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 2-methoxyethanol.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11. 69 (1H, br. s), 8. 27 (1H, d, 7.9 Hz), 8. 10 (1H, d, 8. 5 Hz), 7. 95 (1H, s), 7. 55 (1H, d, 7. 9 Hz), 7. 32 (1H, d, 2. 4 Hz), 7. 05 (1 H, d, 8. 5 Hz), 4. 22 (2H, t, 4. 3 Hz), 3. 67 (2H, t, 4. 3 Hz), 1. 72 (6H, s)

LCMS: m/z 361 [M+H] +

HPLC retention time: 3.38 min (analysis condition W)

Compound A7-9

8-[2-(2-Methoxyethoxy)ethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 2-(2-methoxyethoxy)ethanol.

LCMS: m/z 405 [M+H] +

HPLC retention time: 3.32 min (analysis condition W)

Compound A7-10

6,6-Dimethyl-8-(3-methyloxetan-3-ylmethoxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and 3-chloromethyl-3-methyloxetane.

LCMS: m/z 387 [M+H] +

HPLC retention time: 2.23 min (analysis condition S)

Compound A7-11-1

[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)ethyl]ethyl-carbamic acid tert-butyl ester

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and ethyl-(2-hydroxy-ethyl)-carbamic acid tert-butyl ester.

LCMS: m/z 474 [M+H] +

HPLC retention time: 2.93 min (analysis condition U)

Compound A7-11-2

8-(2-Ethylaminoethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound A7-11-1.

LCMS: m/z 374 [M+H] +

HPLC retention time: 1.35 min (analysis condition U)

Compound A7-12

8-(2-Hydroxyethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and 2-bromo-ethanol.

LCMS: m/z 437 [M+H] +

HPLC retention time: 2.93 min (analysis condition U)

Compound A7-13-1

6,6-Dimethyl-11-oxo-8-(2-phenyl-[1,3]dioxan-5-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 2-phenyl-[1,3]dioxan-5-ol.

LCMS: m/z 465 [M+H] +

HPLC retention time: 4.10 min (analysis condition W)

Compound A7-13-2

8-(2-Hydroxy-1-hydroxymethylethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Anhydrous ferric trichloride (56 mg, 5 eq.) was added to the dichloromethane (2 mL) suspension of 6,6-dimethyl-11-oxo-8-(2-phenyl-[1,3]dioxan-5-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A7-13-1, 13 mg, 0.028 mmol), and stirred at room temperature for 1 hr. The reaction solution was added to water, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by high performance liquid chromatography to obtain the title compound (7 mg, 46%).

LCMS: m/z 377 [M+H] +

HPLC retention time: 2.70 min (analysis condition W)

Compound A7-14-1

8-((S)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and toluene-4-sulfonic acid (R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester.

LCMS: m/z 417 [M+H] +

HPLC retention time: 3.47 min (analysis condition Y)

Compound A7-14-2

8-((R)-2,3-Dihydroxy-propoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To the solution of THF and water (4:1, 1 mL) of 8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A14-1, 30 mg, 0.07 mmol), camphor sulfonic acid (36 mg, 0.14 mmol) was added at room temperature. After stirring at room temperature for 38 hr, the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (dichloromethane/methanol) to obtain the title compound (white solid, 28 mg, 72%).

1 H-NMR (300 MHz, DMSO-d 6 ) σppm; 12. 7 (s, 1H), 8. 31 (d, 1H, J=8.01 Hz), 8. 15 (d, 1H, J=8.77 Hz), 8. 00 (s, 1H), 7. 60 (d, 1H, J=8.01 Hz), 7. 12 (s, 1H), 7. 09 (d, 1H, J=8.77 Hz), 4. 46 (m, 1H), 4. 15 (m, 3H), 3.78 (m, 1H), 1. 76 (s, 6H), 1. 38 (s, 3H), 1. 32 (s, 3H)

LCMS: m/z 377 [M+H] +

HPLC retention time: 1.80 min (analysis condition U)

Compound A7-14-3

8-((S)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-4, the title compound was prepared as a crude product from Compound A7-14-1.

Compound A7-14-4

8-((R)-2,3-Dihydroxy-propoxy)-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-14-2, the title compound was prepared from Compound A7-14-3 (303 mg, 98%).

LCMS: m/z 484 [M+H] +

HPLC retention time: 2.08 min (analysis condition D)

Compound A7-15-1

8-[(4R,5S)-5-(Tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and [(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-methanol.

LCMS: m/z 516 [M+H] +

HPLC retention time: 3.97 min (analysis condition Y)

Compound A7-15-2

6,6-Dimethyl-11-oxo-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-14-2, the title compound was prepared from Compound A7-15-1.

LCMS: m/z 407 [M+H] +

HPLC retention time: 1.73 min (analysis condition U)

Compound A7-16

6,6-Dimethyl-8-(1-methyl-piperidin-4-yloxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 1-methylpiperidin-4-ol.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 75 (1H, s), 8. 32 (1H, d, J=7.9 Hz), 8. 14 (1H, d, J=9.8 Hz), 8. 00 (1H, s), 7. 60 (1H, d, J=7. 9 Hz), 7. 34 (1H, s), 7. 11 (1H, d, J=9.1 Hz), 4. 62 (1H, m), 2. 64 (2H, m), 2. 23 (2H, m), 2. 21 (s, 3H), 1.99 (2H, m), 1. 77 (s, 6H), 1. 73 (2H, m).

LCMS: m/z 400 [M+H] +

HPLC retention time: 1.42 min (analysis condition S)

Compound A7-17

8-(2-Diethylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A6, 25 mg, 0.083 mmol) was dissolved in N,N-dimethylacetamide (1 mL), added with 2-chloroethyldiethylamine (16 mg, 1.1 eq.) and cesium carbonate (54 mg, 2 eq.) in order and stirred at 100° C. for 4 hr. The reaction solution was poured over water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by amino silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (11 mg, 32%).

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8. 32 (1H, d, J=8.2 Hz), 8. 15 (1H, d, J=8. 7 Hz), 8. 01 (1H, s), 7. 61 (1H, d, J=8. 2 Hz), 7. 35 (1H, d, J=1. 8 Hz), 7. 09 (1H, dd, J=8. 7, 1. 8 Hz), 4. 19 (2H, t, J=5. 9 Hz), 2. 83 (2H, t, J=5. 9 Hz), 2. 58 (4H, q, J=7. 0 Hz), 1. 78 (6H, s), 1. 00 (6H, t, J=7.0 Hz)

LCMS: m/z 402 [M+H] +

HPLC retention time: 2.52 min (analysis condition W)

Compound A7-18

N-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl]-acetamide

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and 2-chloroethylacetamide.

LCMS: m/z 388 [M+H] +

HPLC retention time: 2.91 min (analysis condition W)

Compound A7-19

[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl]-carbamic acid ethyl ester

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and ethyl-2-chloroethylcarbamate.

LCMS: m/z 418 [M+H] +

HPLC retention time: 3.35 min (analysis condition W)

Compound A7-20

[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl]-urea

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and 2-chloroethylurea.

LCMS: m/z 399 [M+H] +

HPLC retention time: 2.80 min (analysis condition W)

Compound A7-21

6,6-Dimethyl-8-(oxetan-3-yloxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and toluene-4-sulfonic acid oxetan-3-yl ester.

LCMS: m/z 359 [M+H] +

HPLC retention time: 2.00 min (analysis condition S)

Compound A7-22

6,6-Dimethyl-11-oxo-8-(pyrimidin-2-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and 2-bromopyrimidine.

LCMS: m/z 381 [M+H] +

HPLC retention time: 2.00 min (analysis condition S)

Compound A7-23

(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl acetate ester

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and 3-chloro-propionic acid ethyl ester.

LCMS: m/z 389 [M+H] +

HPLC retention time: 3.37 min (analysis condition U)

Compound A7-24

8-(2-Bromo-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 2-bromoethanol.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 75 (1H, br. s), 8. 32 (1H, d, J=8.2 Hz), 8. 17 (1H, d, J=8. 6 Hz), 8. 01 (1H, s), 7. 61 (1H, dd, J=8. 2, 1. 4 Hz), 7. 40 (1H, d, J=2. 2 Hz), 7. 12 (1H, dd, J=8. 6, 2. 2 Hz), 4. 50 (2H, t, J=5. 3 Hz), 3. 88 (2H, t, J=5. 3 Hz), 1. 77 (6H, s).

LCMS: m/z 409, 411 [M+H] +

HPLC retention time: 2.48 min (analysis condition S)

Compound A7-25

6,6-Dimethyl-11-oxo-8-(piperidin-4-ylmethoxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloric acid salt

Under nitrogen atmosphere, 3-cyano-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound A6, 85 mg, 0.28 mmol) and triphenylphosphine (150 mg, 2 eq.) were added with THF (2 ml), and then further added dropwise with 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (120 mg, 2 eq.) and 2.19 N toluene solution of diethyl azodicarboxylic acid (0.26 mL, 2 eq.). The resultant was stirred at room temperature for 12 hr under nitrogen atmosphere. The residues obtained after concentrating the reaction solution under reduced pressure were purified by silica gel column chromatography (ethyl acetate/dichloromethane) to obtain 4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (white powder, 120 mg).

To the resulting compound, 4 N hydrochloric acid and dioxane solution was added under cooling. After stirring at room temperature for 2 hr, the solvent was removed under nitrogen stream. Then, the residues were washed with diethyl ether and then subjected to azeotropic treatment with toluene, followed by drying under vacuum and filtration to obtain the title compound (79 mg).

LCMS: m/z 399 [M+H] +

HPLC retention time: 2.22 min (analysis condition C)

Compound A8-1

6,6-Dimethyl-11-oxo-8-(piperidin-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

THF (0.5 mL) and TFA (0.5 mL) were added to 4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (Compound A7-1, 35 mg, 0.072 mmol), and the mixture was stirred at room temperature until Compound A7-1 disappears. The reaction solution was concentrated under reduced pressure and the residue was desalinated by using anion exchanger PL StratoSpheres (trademark) PL-HCO3 MP to obtain the title compound (37 mg, 76%).

1 H-NMR (400 MHz, CD 3 OD) δ: 8. 38 (1H, d, J=7.9 Hz), 8. 24 (1H, d, J=8. 5 Hz), 7. 85 (1H, s), 7. 53 (1H, d, J=7.9 Hz), 7. 27 (1H, s), 7. 09 (1H, d, J=8.5 Hz), 4. 67-4. 76 (1H, m), 3.07-3. 20 (2H, m), 2.77-2. 87 (2H, m), 2.03-2. 15 (2H, m), 1. 80 (6H, s), 1.69-1. 77 (2H, m)

LCMS: m/z 386 [M+H] +

HPLC retention time: 2.51 min (analysis condition W)

Compound A8-2

8-(2-Amino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound A7-3.

LCMS: m/z 346 [M+H] +

HPLC retention time: 2.40 min (analysis condition W)

Compound A8-3

8-(2-Methanesulfonyl-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-8, the title compound was prepared from Compound A7-5.

LCMS: m/z 409 [M+H] +

HPLC retention time: 3.13 min (analysis condition W)

Compound A8-4

8-(2-Methanesulfinyl-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

The title compound was obtained as a by-product of the synthesis of Compound A8-3.

LCMS: m/z 393 [M+H] +

HPLC retention time: 2.87 min (analysis condition W)

Compound A8-5

5,6,6-Trimethyl-11-oxo-8-(tetrahydro-pyran-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A10-1, the title compound was prepared from Compound A7-6.

LCMS: m/z 401 [M+H] +

HPLC retention time: 2.72 min (analysis condition S)

Compound A8-6-1

2-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

8-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A5-2, 50 mg, 0.158 mmol) was dissolved in CH 3 CN (1 mL), added with NBS (56 mg, 2 eq.), and stirred at 80° C. overnight. The reaction solution was added to water, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were added with MeOH and the solid remained after dissolution was filtered to obtain the target compound (yellow powder, 20 mg, 38%).

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 92 (1H, s), 8. 50 (1H, s), 8. 16 (1H, d, J=8. 5 Hz), 8. 14 (1H, s), 7. 36 (1H, d, J=2. 4 Hz), 7. 11 (1H, dd, J=8. 5, 2. 4 Hz), 3. 92 (3H, s), 1. 78 (6H, s).

LCMS: m/z 395, 397 [M+H] +

HPLC retention time: 2.57 min (analysis condition S)

Compound A8-6-2

2-Bromo-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A6, the title compound was prepared from Compound A8-6-1.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8. 46 (1H, s), 8. 10 (1H, s), 8. 05 (1H, d, J=8.6 Hz), 7. 13 (1H, d, J=2.1 Hz), 6. 89 (1H, dd, J=8.5, 2.1 Hz), 1. 71 (6H, s).

LCMS: m/z 381, 383 [M+H] +

HPLC retention time: 2.10 min (analysis condition S)

Compound A8-6-3

2-Bromo-8-(2-diethylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A8-6-2.

1 H-NMR (400 MHz, CD 3 OD) δ: 8. 53 (1H, d, J=0.5 Hz), 8. 20 (1H, d, J=8. 7 Hz), 7. 88 (1H, d, J=0. 5 Hz), 7. 28 (1H, d, J=2. 3 Hz), 7. 05 (1H, dd, J=8. 9, 2. 5 Hz), 4. 24 (2H, t, J=5. 7 Hz), 2. 96 (2H, t, J=5. 7 Hz), 2. 70 (4H, q, J=7.1 Hz), 1.79 (6H, s), 1. 12 (6H, t, J=7. 2 Hz).

LCMS: m/z 480, 482 [M+H] +

HPLC retention time: 1.73 min (analysis condition S)

Compound A8-7

(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetic acid

(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl acetate ester (Compound A7-23, 180 mg, 0.464 mmol) and potassium hydroxide (130 mg, 2.32 mmol) were dissolved in THF (10 ml) and water (1.8 mL), and stirred at 70° C. for 2 hr. After cooling to room temperature, the mixture was extracted with dichloromethane. Water layer( ) was adjusted to be acidic by using 1 N hydrochloric acid, and the precipitated solid was filtered and washed several times with water to obtain the title compound (white solid, 130 mg, 78%).

1 H-NMR (300 MHz, DMSO) σppm 13. 09 (s, 1H), 8. 31 (d, 1H, J=8.1 Hz), 8. 11 (d, 1H, J=8.4 Hz), 8. 01 (s, 1H), 7. 58 (d, 1H, J=7.8 Hz), 7.25 (d, 1H, J=2.1 Hz), 6. 97 (d, 1H, J=8.4 Hz), 4. 51 (s, 2H), 1. 73 (s, 6H)

LCMS: m/z 361 [M+H] +

HPLC retention time: 2.97 min (analysis condition U)

Compound A8-8

6,6-Dimethyl-8-(2-morpholin-4-yl-ethoxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-17, the title compound was prepared from Compound A7-24 and morpholine.

1 H-NMR (500 MHz, CD 3 OD+CDCl 3 ) σppm; 8. 4 (d, 1H, J=8.2 Hz), 8. 3 (d, 1H, J=8.7 Hz), 7.8 (s, 1H), 7. 5 (dd, 1H, J=1.1 Hz, J=8.2 Hz), 7. 2 (d, 1H, J=2.3 Hz), 7. 0 (dd, 1H, J=2.2 Hz, J=8.7 Hz), 4. 2 (t, 2H, J=5.3 Hz), 3. 7 (t, 4H, J=4.5 Hz), 2. 9 (t, 2H, J=5. 3 Hz), 2. 6 (t, 4H, J=4.5 Hz), 1. 8 (s, 6H)

LCMS: m/z 416 [M+H] +

HPLC retention time: 2.40 min (analysis condition U)

Compound A8-9

8-[2-(1,1-Dioxothiomorpholino)-ethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A7-24 and thiomorpholine-1,1-dioxide.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 72 (1H, s), 8. 31 (1H, d, 8.5 Hz), 8. 15 (1H, d, 8. 5 Hz), 8. 00 (1H, s), 7. 60 (1H, d, 8. 5 Hz), 7. 36 (1H, d, 1. 8 Hz), 7. 10 (1H, dd, 1. 8, 8. 5), 4. 25 (2H, t, 5.5 Hz), 3.06-3. 33 (8H, m), 2. 97 (2H, t, 5. 5), 1.77 (6H, s)

LCMS: m/z 464 [M+H] +

HPLC retention time: 2.70 min (analysis condition W)

Compound A8-10

8-(2-Tert-butylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A7-24 and tert-butylamine.

1 H-NMR (400 MHz, DMSO-d6) δ: 12. 71 (1H, s), 8. 32 (1H, d, 7.9 Hz), 8. 15 (1H, d, 9. 1 Hz), 8. 07 (1 d, 1. 8 Hz), 7. 60 (1H, dd, 1. 8, 7. 9 Hz), 7. 35 (1H, d, 2. 4 Hz), 7. 09 (1H, dd, 2. 4, 9.1 Hz), 4. 16 (2H, t, 6.1 Hz), 2. 91 (2H, t, 6.1 Hz), 1.77 (6H, s), 1. 08 (9H, s)

LCMS: m/z 402 [M+H] +

HPLC retention time: 2.55 min (analysis condition W)

Compound A8-11

8-(2-Sec-butylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-17, the title compound was prepared from Compound A7-24 and sec-butylamine.

LCMS: m/z 402 [M+H] +

HPLC retention time: 1.88 min (analysis condition U)

Compound A8-12

8-[2-(2-Hydroxy-1,1-dimethyl-ethylamino)-ethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-17, the title compound was prepared from Compound A7-24 and 2-amino-2-methyl-propan-1-ol.

1 H-NMR (300 MHz, DMSO-d 6 ) σppm; 12. 65 (brs, 1H), 8. 31 (d, 1H, J=8.0 Hz), 8. 15 (d, 1H, J=8.8 Hz), 7. 99 (s, 1H), 7. 59 (d, 1H, J=8.0 Hz), 7. 34 (d, 1H, J=2.3 Hz), 7. 08 (dd, 1H, J=2.2 Hz, J=8.8 Hz), 4. 58 (brs, 1H), 4. 16 (t, 2H, J=5.7 Hz), 3. 20 (s, 2H), 2. 88 (t, 2H, J=5.7 Hz), 1. 76 (s, 6H), 0.97 (s, 6H)

LCMS: m/z 418 [M+H] +

HPLC retention time: 2.47 min (analysis condition U)

Compound A8-13

8-[2-(4-Ethyl-piperazin-1-yl)-ethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-17, the title compound was prepared from Compound A7-24 and 1-ethyl-piperazine.

LCMS: m/z 443 [M+H] +

HPLC retention time: 1.68 min (analysis condition U)

Compound A8-14

8-(2-Imidazol-1-yl-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 2-imidazol-1-yl-ethanol.

1 H-NMR (300 MHz, DMSO-d6) σppm; 12. 71 (s, 1H), 8. 31 (d, 1H, J=8.3 Hz), 8. 14 (d, 1H, J=8.8 Hz), 7. 99 (s, 1H), 7. 73 (s, 1H), 7. 60 (d, 1H, J=8.3 Hz), 7. 34 (s, 1H), 7. 29 (s, 1H), 7. 09 (d, 1H, J=8.8 Hz), 6. 91 (s, 1H), 4. 20 (s, 4H), 1. 76 (s, 6H)

LCMS: m/z 387 [M+H] +

HPLC retention time: 1.77 min (analysis condition U)

Compound A8-15

8-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethoxy}-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

According to the same method as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A7-24 and 2-(2-hydroxy-ethylamino)-ethanol.

LCMS: m/z 434 [M+H] +

HPLC retention time: 2.40 min (analysis condition U)

Compound A8-16

1-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl]-piperidine-4-carboxylic acid amide

Under the same conditions as the method for synthesizing Compound A8-17, the title compound was prepared from Compound A7-24 and piperidine-4-carboxylic acid amide.

LCMS: m/z 457 [M+H] +

HPLC retention time: 1.28 min (analysis condition S)

Compound A8-17

6,6-Dimethyl-11-oxo-8-[2-(3-oxo-piperazin-1-yl)-ethoxy]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To DMF solution (5 mL) of 8-(2-bromo-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A7-24, 30 mg, 0.07 mmol), piperazin-2-one (44.9 mg, 0.35 mmol) and N,N-diisopropylethylamine (0.061 mL, 0.35 mmol) were added at room temperature and stirred at 80° C. for 18 hr. After cooling to room temperature, the mixture was extracted with ethyl acetate washed with saturated brine. The organic layer was dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by preparative TLC (dichloromethane/methanol) to obtain the title compound (white solid, 24 mg, 80%).

1 H-NMR (300 MHz, DMSO-d6) σppm; 12. 71 (s, 1H), 8. 32 (d, 1H, J=8.4 Hz), 8. 15 (d, 1H, J=8.8 Hz), 8. 00 (s, 1H), 7. 75 (s, 1H), 7. 60 (d, 1H, J=8.4 Hz), 7. 37 (d, 1H, J=2.3 Hz), 7. 09 (dd, 1H, J=2.3 Hz, J=8.8 Hz), 4. 27 (t, 2H, J=5.7 Hz), 3. 19 (m, 2H), 3. 08 (s, 2H), 2. 83 (t, 2H, J=5.7 Hz), 2. 70 (t, 2H, J=5.7 Hz), 1. 8 (s, 6H)

LCMS: m/z 429 [M+H] +

HPLC retention time: 1.29 min (analysis condition S)

Compound A8-18

Morpholine-4-sulfonic acid[2-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl]-amide

The title compound was obtained as a by-product of the synthesis of Compound C1-2.

LCMS: m/z 495 [M+H] +

HPLC retention time: 2.00 min (analysis condition S)

Compound A8-19

4-Methyl-piperazine-1-sulfonic acid[2-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl]-amide

The title compound was obtained as a by-product of the synthesis of Compound C1-4.

1 H-NMR (300 MHz, DMSO-d6) δ: 1. 77 (6H, s), 2. 16 (3H, s), 2. 34 (4H, m), 3. 08 (4H, m), 3. 35 (2H, m), 4. 19 (2H, t, 5.34 Hz), 7. 09 (1H, dd, 8.77 Hz, 2.99 Hz), 7. 37 (1H, bs, 1.91 Hz), 7. 59 (2H, m), 8. 01 (1H, s), 8. 16 (1H, d, 8.40 Hz), 8. 32 (1H, d, 8.01 Hz), 12. 7 (1H, s).

LCMS: m/z 501 [M+H] +

HPLC retention time: 1.43 min (analysis condition S)

Compound A8-20

6,6-Dimethyl-8-(1-oxetan-3-yl-piperidin-4-ylmethoxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

6,6-Dimethyl-11-oxo-8-(piperidin-4-ylmethoxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloric acid salt (Compound A7-25, 30 mg, 0.075 mmol) and oxetan-3-one (38 mg, 7 eq.) were dissolved in acetic acid (0.2 ml), THF (1 ml) and methanol (1 ml), added with sodium cyanoborohydride (33 mg, 7 eq.) at room temperature, and stirred overnight. The reaction solution was added with water, and then extracted with ethyl acetate. The solution was dried over sodium sulfate and the solvent was removed under vacuum and the resulting residues were purified by preparative TLC (chloroform:2 N ammonia methanol=9:1) to obtain the target compound (15 mg).

LCMS: m/z 456 [M+H] +

HPLC retention time: 2.78 min (analysis condition C)

Compound A8-21

6,6-Dimethyl-8-[2-(1-oxetan-3-yl-piperidin-4-yl)-ethoxy]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-25, and Compound A8-20, the title compound was prepared from Compound A6 and 4-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (15 mg).

LCMS: m/z 470 [M+H] +

HPLC retention time: 2.85 min (analysis condition C)

Compound A9-1

N-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl]-methanesulfonamide

Trifluoroacetic acid salt of 8-(2-amino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A8-2, 19 mg, 0.044 mmol) was suspended in dichloromethane (0.5 mL), added with diisopropylethylamine (0.0157 mL, 2 eq.) and methanesulfonyl chloride (0.0034 mL, 1 eq.), and then stirred at room temperature for 2 hr. The reaction solution was added to water, and then extracted with dichloromethane. After washing with saturated brine, the organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were separated by silica gel preparative TLC (ethyl acetate 100%) to obtain the target compound (5.5 mg, 29%).

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8. 47 (1H, d, J=8.2 Hz), 8. 32 (1H, d, J=8. 7 Hz), 8.16 (1H, s), 7. 76 (1H, d, J=8.2 Hz), 7.53-7. 46 (2H, m), 7. 26 (1H, d, J=8.7 Hz), 4.39-4. 33 (2H, m), 3.58-3. 51 (2H, m), 3. 12 (3H, s), 1. 93 (6H, s)

LCMS: m/z 424 [M+H] +

HPLC retention time: 3.10 min (analysis condition W)

Compound A9-2

N-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-ethyl]-2,2,2-trifluoro-acetamide

The title compound was obtained as a by-product of the synthesis of Compound A9-1.

LCMS: m/z 442 [M+H] +

HPLC retention time: 3.45 min (analysis condition W)

Compound A9-3-1

8-{2-(Tert-butyloxycarbonylaminosulfonyl)amino-ethoxy}-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Trifluoroacetic acid salt of 8-(2-amino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A8-2, 20 mg, 0.044 mmol) was dissolved in pyridine (0.5 mL), added with N-(tert-butoxycarbonyl)-N-[4-(dimethyl azaniumylidene)-1,4-dihydropyridin-1-yl sulfonyl]azanide (13.5 mg, 1 eq.), and then stirred at room temperature for 14 hr. The reaction solution was added to water, and then extracted with ethyl acetate. After washing with saturated brine, the organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were separated by silica gel preparative TLC (ethyl acetate) to obtain the title compound (16.1 mg, 68%).

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 74 (1H, s), 10. 94 (1H, s), 8. 33 (1H, d, J=8.5 Hz), 8. 16 (1H, d, J=9.1 Hz), 8. 02 (1H, s), 7. 84 (1H, br. s), 7. 62 (1H, d, J=7.9 Hz), 7. 36 (1H, s), 7. 10 (1H, d, J=7.9 Hz). 4.24-4. 18 (2H, m), 1.78 (6H, s), 1.32 (9H, s)

LCMS: m/z 525 [M+H] +

HPLC retention time: 3.48 min (analysis condition W)

Compound A9-3-2

8-{2-(Methylaminosulfonyl)amino-ethoxy}-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound A9-3-1.

LCMS: m/z 425 [M+H] +

HPLC retention time: 2.95 min (analysis condition W)

Compound A9-4

8-(1-Methanesulfonyl-piperidin-4-yloxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

According to the same method as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A8-1 and methanesulfonyl chloride.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 72 (1H, s), 8. 30 (1H, d, J=8.5 Hz), 8. 14 (1H, d, J=8. 5 Hz), 8. 00 (1H, s), 7. 59 (1H, d, J=7. 9 Hz), 7. 38 (1H, s), 7. 13 (1H, d, J=8.5 Hz), 4. 81 (1H, s), 3.39-3. 38 (2H, m), 3.19-3. 13 (2H, m), 2. 93 (3H, s), 2. 11-2. 04 (2H, m), 1.83-1. 75 (8H, m).

LCMS: m/z 464 [M+H] +

HPLC retention time: 3.41 min (analysis condition U)

Compound A9-5

8-[1-(2-Methoxy-ethyl)-piperidin-4-yloxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A9-1, the title compound was prepared from Compound A8-1 and 1-bromo-2-methoxy-ethane.

1 H-NMR (400 MHz, CDCl 3 ) δ: 8.48-8. 53 (1H, m), 8.32-8. 38 (1H, m), 7. 74-7. 77 (1H, m), 7.50-7. 55 (1H, m), 7.07-7. 10 (1H, m), 6.95-7. 00 (1H, m), 4.43-4. 51 (1H, m), 3. 53 (2H, t, J=5.6 Hz), 3. 36 (3H, s), 2.77-2. 87 (2H, m), 2. 62 (2H, t, J=5. 6 Hz), 2.35-2. 47 (2H, m), 2.02-2. 12 (2H, m), 1.78-1. 95 (2H, m), 1. 82 (6H, s).

LCMS: m/z 444 [M+H] +

HPLC retention time: 2.00 min (analysis condition U)

Compound A9-6-2

8-[1-(2-Hydroxy-ethyl)-piperidin-4-yloxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

According to the same method as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A8-1 and (2-bromoethoxy)-tert-butyldimethylsilane, followed by treatment with tetrabutylammonium fluoride.

LCMS: m/z 430 [M+H] +

HPLC retention time: 1.45 min (analysis condition S)

Compound A9-7

8-[1-(2-Fluoro-ethyl)-piperidin-4-yloxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

According to the same method as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A8-1 and methanesulfonic acid 2-fluoroethyl ester.

1 H-NMR (300 MHz, DMSO-d6) δ: 1. 67 (2H, m), 1. 76 (6H, s), 2. 01 (2H, m), 2. 37 (2H, t, 11. 0 Hz), 2. 61 (1H, t, 4.20 Hz), 2. 70 (1H, t, 4. 58), 2. 78 (2H, m), 4. 46 (1H, t, 4.58 Hz), 4. 62 (2H, t, 5.34 Hz), 7. 10 (1H, dd, 9.16 Hz, 2.29 Hz), 7. 34 (1H, bs, 1. 53 Hz), 7. 60 (1H, dd, 8.40 Hz, 1.53 Hz), 7. 99 (1H, s), 8. 13 (1H, d, 8.39 Hz), 8. 30 (1H, d, 8.39 Hz), 12. 7 (1H, s).

LCMS: m/z 432 [M+H] +

HPLC retention time: 1.52 min (analysis condition S)

Compound A9-8

8-(1-Acetyl-piperidin-4-yloxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

According to the same method as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A8-1 and acetyl chloride.

LCMS: m/z 428 [M+H] +

HPLC retention time: 1.91 min (analysis condition S)

Compound A9-9

2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetamide

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and 2-bromo-acetamide.

LCMS: m/z 360 [M+H] +

HPLC retention time: 2.83 min (analysis condition U)

Compound A9-10

2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-N-methyl-acetamide

(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetic acid (Compound A8-7, 30 mg, 0.0838 mmol), methylamine hydrochloric acid salt (28.1 mg, 0.417 mmol), EDC (32 mg, 0.167 mmol) and HOBT (0.023 mg, 0.167 mmol) were dissolved in DMF (1 mL), and added with diisopropylethylamine (0.145 mL, 0.833 mmol) at room temperature. After stirring at room temperature for 18 hr, water was added and the extraction was carried out with ethyl acetate. After washing with saturated brine, the organic layer was dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were dissolved in dichloromethane, added with diethyl ether, and the precipitated title compound was obtained (white solid, 19.7 mg, 63%).

1 H-NMR (300 MHz, DMSO) σ ppm 12. 73 (s, 1H), 8. 33 (d, 1H, J=8.1 Hz), 8. 17 (d, 1H, J=8.7 Hz), 8. 13 (s, 1H), 8. 00 (s, 1H), 7. 62 (d, 1H, J=8.1 Hz), 7. 39 (d, 1H, J=2. 4 Hz), 7. 11 (dd, 1H, J=8.7 Hz, 2.4 Hz), 4. 64 (s, 2H), 3. 17 (d, 1H, J=5.4 Hz), 2. 69 (d, 1H, J=4.5 Hz), 1. 76 (s, 6H)

LCMS: m/z 374 [M+H] +

HPLC retention time: 2.43 min (analysis condition U)

Compound A9-11

2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-acetamide

Under the same conditions as the method for synthesizing Compound A9-10, the title compound was prepared from Compound A8-7 and C-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methylamine.

LCMS: m/z 474 [M+H] +

HPLC retention time: 2.20 min (analysis condition U)

Compound A9-12

2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-N-(2,3-dihydroxy-propyl)-acetamide

Under the same conditions as the method for synthesizing Compound A7-14-2, the title compound was prepared from Compound A9-11.

LCMS: m/z 434 [M+H] +

HPLC retention time: 1.72 min (analysis condition U)

Compound A9-13

2-Methyl-acrylic acid 2-[2-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetylamino]-ethyl ester

Under the same conditions as the method for synthesizing Compound A9-10, the title compound was prepared from Compound A8-7 and 2-methyl-acrylic acid 2-amino-ethyl ester.

LCMS: m/z 472 [M+H] +

HPLC retention time: 3.30 min (analysis condition U)

Compound A9-14

2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-N-(2-hydroxy-ethyl)-acetamide

2-Methyl-acrylic acid 2-[2-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetylamino]-ethyl ester (Compound A9-13, 40 mg, 0.085 mmol) was dissolved in a mixture solvent of methanol (2 mL) and water (2 mL), added with potassium hydroxide (48 mg, 0.85 mmol), and then stirred at room temperature for 18 hr. After the neutralization with 1 N hydrochloric acid, the reaction solution was concentrated under reduced pressure. The resulting residues were purified by amino silica gel to obtain the title compound (white solid, 8.9 mg, 26%).

1 H-NMR (300 MHz, DMSO) σ ppm 12. 75 (s, 1H), 8. 32 (d, 1H, J=8.1 Hz), 8. 17-8. 13 (m, 2 Hz), 7. 99 (s, 1H), 7. 60 (d, 1H, J=8.1 Hz), 7. 38 (d, 1H, J=1.8 Hz), 7. 11 (dd, 1H, J=2.1 Hz, 8.7 Hz), 4. 72 (t, 1H, J=5.7 Hz), 4. 65 (s, 1H), 3. 48 (dd, 2H, J=12.0 Hz, 6. 0 Hz), 3. 26 (dd, 2H, J=12.0 Hz, 6.0 Hz), 1. 76 (s, 6H)

LCMS: m/z 404 [M+H] +

HPLC retention time: 2.83 min (analysis condition U)

Compound A9-15-1

4-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester

(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetic acid (Compound A8-7, 30 mg, 0.083 mmol), piperazine-1-carboxylic acid tert-butyl ester (31 mg, 2 eq.), and HOBt (30 mg, 3 eq.) were dissolved in 0.5 ml DMF, added with EDC (48 mg, 3 eq.), and stirred at room temperature overnight. Thereafter, the solvent was removed under reduced pressure and the resulting residues were purified by preparative TLC to obtain the title compound (20 mg).

LCMS: m/z 527, 471, 427 [M−H] −

HPLC retention time: 2.77 min (analysis condition C)

Compound A9-15-2

6,6-Dimethyl-11-oxo-8-(2-oxo-2-piperazin-1-yl-ethoxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloric acid salt

4-[2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester (Compound A9-15-1, 20 mg) was added with 4 N hydrochloric acid and dioxane solution (1 ml), and stirred in an water bath at 10° C. for 4 hr. Water was added to the reaction solution and the resulting precipitates were filtered and dried to obtain the title compound (15 mg, white powder).

LCMS: m/z 429 [M+H] +

HPLC retention time: 0.81 min (analysis condition I)

Compound A9-16

2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-N-(2-cyano-ethyl)-acetamide

(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetic acid (Compound A8-7, 30 mg, 0.083 mmol), 3-aminopropionitrile (12 mg, 2 eq.) and HOBt (30 mg, 3 eq.) were dissolved in 0.5 ml DMF, added with EDC (48 mg, 3 eq.), and stirred at room temperature overnight. Thereafter, the solvent was removed under reduced pressure and the resulting residues were purified by preparative TLC to obtain the title compound (23 mg).

LCMS: m/z 411 [M+H] +

HPLC retention time: 2.27 min (analysis condition C)

Compound A9-17

2-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-N-(2-cyano-ethyl)-N-methyl-acetamide

(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetic acid (Compound A8-7, 30 mg, 0.083 mmol), N-methyl-3-aminopropionitrile (14 mg, 2 eq.) and HOBt (30 mg, 3 eq.) were dissolved in 0.5 ml DMF, added with EDC (48 mg, 3 eq.), and stirred at room temperature overnight. Thereafter, the solvent was removed under reduced pressure and the resulting residues were purified by preparative TLC to obtain the title compound (7 mg).

LCMS: m/z 411 [M+H] +

HPLC retention time: 2.33 min (analysis condition C)

Compound A10

8-(Tert-butyl-dimethyl-silanyloxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

The DMF solution of 8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A6, 100 mg, 0.331 mmol), imidazole (67.5 mg, 3 eq.) and tert-butylchlorodimethylsilane (92.4 mg, 1.5 eq.) was stirred overnight at room temperature. To the reaction solution, saturated aqueous solution of sodium hydrogen carbonate was added followed by extraction with tert-butylmethyl ether. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the target compound (white solid, 170 mg, 100%).

LCMS: m/z 417 [M+H] +

HPLC retention time: 3.38 min (analysis condition S)

Compound A10-1

8-Methoxy-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To the THF solution of triphenylphosphine (260 mg, 3 eq.), azodicarboxylic acid diisopropyl ester (0.195 ml, 3 eq.) was added and the mixture was stirred at room temperature for 1 hr. Thereafter, 8-(tert-butyldimethylsilanyloxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A10, 138 mg, 0.331 mmol) and methanol (1 ml) were added and stirred overnight. The reaction solution was purified by HPLC to obtain the target compound (44.8 mg, 41%).

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 44 (1H, d, J=8.1 Hz), 8. 33 (1H, s), 8. 14 (1H, d, J=8.7 Hz), 7. 66 (1H, dd, J=8.2, 1.1 Hz), 7. 39 (1H, d, J=2.3 Hz), 7. 09 (1H, dd, J=8.7, 2.3 Hz), 4. 17 (3H, s), 3. 92 (3H, s), 1. 88 (6H, s).

LCMS: m/z 331 [M+H] +

HPLC retention time: 2.35 min (analysis condition S)

Compound A10-2

8-(1-Methanesulfonyl-piperidin-4-yloxy)-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-4, the title compound was prepared from Compound A9-4.

LCMS: m/z 478 [M+H] +

HPLC retention time: 2.68 min (analysis condition U)

Compound B1

Trifluoro-methanesulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester

8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A6, 550 mg, 0.189 mmol) was dissolved in pyridine (18 mL), added with anhydrous trifluoromethanesulfonic acid (0.758 ml, 3 eq.), and stirred at room temperature for 30 min. The reaction solution was added to water and then extracted with dichloromethane. The organic layer was dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the target compound (white powder, 641 mg, 81%).

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 89 (1H, br. s), 8. 36 (1H, d, J=8.8 Hz), 8. 31 (1H, dd, J=8. 1, 0. 7 Hz), 8. 11 (1H, d, J=2. 3 Hz), 8. 04 (1H, dd, J=1. 5, 0. 7 Hz), 7.65-7. 60 (2H, m). 1. 76 (6H, s)

LCMS: m/z 435 [M+H] +

HPLC retention time: 3.10 min (analysis condition U)

Compound B2-1

8-(4-Isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Trifluoro-methanesulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 40 mg, 0.0921 mmol) was dissolved in NMP (1 ml) and added with 1-isopropylpiperazine (236 mg, 20 eq.). The mixture was stirred at 120° C. for 3 hr. After cooling to room temperature, purification was carried out by HPLC to obtain the target compound (white powder, 12.8 mg, 34%).

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 30 (1H, d, 8.1 Hz), 8. 03 (1H, d, 8.6 Hz), 7. 98 (1H, s), 7. 56 (1H, d, 8.6 Hz), 7. 21 (1H, s), 7. 04 (1H, d, 9.1 Hz), 3.40-3. 37 (4H, m), 2.73-2. 65 (1H, m), 2.61-2. 58 (4H, m), 1. 75 (6H, s), 1. 02 (6H, d, 6.6 Hz)

LCMS: m/z 413 [M+H] +

Compound B2-2

8-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

According to the same method as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and N-(2-hydroxyethyl)piperazine.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 30 (1H, d, 8.1 Hz), 8. 03 (1H, d, 8.7 Hz), 7. 99 (1H, s), 7. 58 (1H, d, 7.9 Hz), 7. 21 (1H, s), 7. 04 (1H, d, 8.7 Hz), 4.50-4. 46 (1H, br m), 3.59-3. 53 (2H, m), 3.39-3. 35 (4H, m), 2.59-2. 56 (4H, m), 2. 45 (2H, t, 6. 1 Hz), 1.76 (6H, s)

LCMS: m/z 415 [M+H] +

HPLC retention time: 1.27 min (analysis condition S)

Compound B2-3

6,6-Dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and morpholine.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 62 (1H, br. s), 8. 29 (1H, d, 8.2 Hz), 8. 04 (1H, d, 9.0 Hz), 7. 96 (1H, s), 7. 56 (1H, d, 8.2 Hz), 7. 22 (1H, s), 7. 04 (1H, d, 9. 0 Hz), 3.77-3. 75 (4H, m), 3.35-3. 30 (4H, m), 1. 74 (6H, s)

LCMS: m/z 372 [M+H] +

HPLC retention time: 2.45 min (analysis condition U)

Compound B2-4

6,6-Dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and 4-pyrrolidin-1-yl-piperidine.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 30 (1H, d, 8.1 Hz), 8. 01 (1H, d, 8.7 Hz), 7. 97 (1H, s), 7. 56 (1H, d, 8.6 Hz), 7. 20 (1H, s), 3.94-3. 90 (2H, m), 3.30-3. 28 (4H, m), 2. 95 (2H, t, 11. 8 Hz), 2.24-2. 20 (1H, m), 1.95-1. 91 (2H, m), 1. 75 (6H, s), 1.70-1. 66 (4H, m), 1.54-1. 52 (2H, m)

LCMS: m/z 439 [M+H] +

Compound B2-5-1

4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperazine-1-carboxylic acid tert-butyl ester

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and piperazine-1-carboxylic acid tert-butyl ester.

LCMS: m/z 471 [M+H] +

HPLC retention time: 2.67 min (analysis condition S)

Compound B2-5-2

6,6-Dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound B2-5-1.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8. 32 (1H, d, 8.5 Hz), 8. 03 (1H, d, 9.1 Hz), 7. 99 (1H, s), 7. 59 (1H, dd, 8. 2, 1. 5 Hz), 7. 20 (1H, d, 2. 4 Hz), 7. 04 (1H, dd, 8. 8, 2. 1 Hz), 3.32-3. 30 (4H, m), 2.88-2. 87 (4H, m), 1. 77 (6H, s)

LCMS: m/z 371 [M+H] +

Compound B2-6

6,6-Dimethyl-11-oxo-8-piperidin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and piperidine.

LCMS: m/z 370 [M+H] +

HPLC retention time: 2.40 min (analysis condition U)

Compound B2-7-1

8-(4-Hydroxy-piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and piperidin-4-ol.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 30 (1H, d, 8.1 Hz), 8. 01 (1H, d, 8.7 Hz), 7. 97 (1H, s), 7. 56 (1H, d, 7.7 Hz), 7. 19 (1H, s), 7. 04 (1H, d, 10. 6 Hz), 4.76-4. 71 (1H, br m), 3.81-3. 75 (3H, m), 3. 08 (2H, t, 10. 2 Hz), 1.86-1. 82 (2H, m), 1.75 (6H, s), 1.49-1.42 (2H, m)

LCMS: m/z 386 [M+H] +

Compound B2-7-2

6,6-Dimethyl-11-oxo-8-(4-oxo-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

8-(4-Hydroxy-piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound B2-7-1, 210 mg, 0.545 mmol), was dissolved in the DCM (2 mL) and DMF (0.6 mL) mixture solvent, added with 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (300 mg, 1.3 eq.), and the mixture was stirred at room temperature for 2 hr. To the reaction solution, 0.25 mol/L aqueous solution of sodium thiosulfate, saturated sodium bicarbonate solution and CPME were added followed by further stirring at room temperature for 1 hr. The reaction solution was filtered and the filtrate was subjected to liquid separation. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the target compound (yellowish white powder, 109 mg, 52%).

LCMS: m/z 384 [M+H] +

HPLC retention time: 2.17 min (analysis condition U)

Compound B2-8

8-(4-Methanesulfonyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and 1-methanesulfonylpiperazine.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 66 (1H, br. s), 8. 31 (1H, d, J=8.2 Hz), 8. 06 (1H, d, J=8. 7 Hz), 7. 99 (1H, s), 7. 59 (1H, d, J=8. 2 Hz), 7. 30 (1H, d, J=1.8 Hz), 7. 09 (1H, dd, J=8.7, 1.8 Hz), 3. 53 (4H, t, J=4.8 Hz), 3. 27 (4H, t, J=4.8 Hz), 2. 94 (3H, s), 1. 77 (6H, s).

LCMS: m/z 449 [M+H] +

HPLC retention time: 1.98 min (analysis condition S)

Compound B2-9

8-(3-Methanesulfonyl-pyrrolidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and 3-methanesulfonylpyrrolidine.

LCMS: m/z 434 [M+H] +

HPLC retention time: 1.83 min (analysis condition S)

Compound B2-10

8-(1,1-Dioxothiomorpholino)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Trifluoro-methanesulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 30 mg, 0.069 mmol) was dissolved in 1,4-dioxane (1 mL), added with thiomorpholine 1,1-dioxide (19 mg, 2 eq.), Pd 2 (dba) 3 (6.3 mg, 0.1 eq.), BINAP (8.6 mg, 0.2 eq.) and K 3 PO 4 (29 mg, 2 eq.), and stirred at 100° C. overnight. The reaction solution was added to water, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the target compound (white powder, 2.1 mg, 7%).

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 29 (1H, d, J=8.6 Hz), 8. 07 (1H, d, J=8. 9 Hz), 8.00 (1H, s), 7. 55 (1H, dd, J=8. 5, 1. 7 Hz), 7. 34 (1H, d, J=2. 0 Hz), 7. 15 (1H, dd, J=9.1, 2.7 Hz), 4. 01 (4H, s), 3. 16 (4H, s), 1. 77 (6H, s).

LCMS: m/z 420 [M+H] +

HPLC retention time: 1.80 min (analysis condition S)

Compound B2-11

8-(4-Cyclopentyl-2-oxo-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-10, the title compound was prepared from Compound B1 and 4-cyclopentylpiperazin-2-one.

LCMS: m/z 453 [M+H] +

HPLC retention time: 1.30 min (analysis condition S)

Compound B2-12

6,6-Dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and 4-piperidin-4-yl morpholine.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 73 (1H, s), 8.27-8. 31 (1H, m), 7.98-8. 02 (1H, m), 7.95-7. 97 (1H, m), 7.53-7. 58 (1H, m), 7.17-7. 21 (1H, m), 6.99-7. 05 (1H, m), 3.97-4. 05 (2H, m), 3.53-3. 59 (4H, m), 2.80-2. 90 (2H, m), 2.43-2. 51 (4H, m), 2.31-2. 40 (1H, m), 1.83-1. 92 (2H, m), 1. 74 (6H, s), 1.39-1. 52 (2H, m)

LCMS: m/z 455 [M+H] +

HPLC retention time: 1.73 min (analysis condition U)

Compound B2-13

8-(4,4-Difluoro-1,4′-bipiperidin-1′-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound B2-7-2 and 4,4-difluoropiperidine hydrochloric acid salt.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 59 (1H, s), 8.25-8. 32 (1H, m), 7.97-8. 02 (1H, m), 7. 96 (1H, s), 7.52-7. 59 (1H, m), 7.16-7. 21 (1H, m), 6.99-7. 05 (1H, m/z), 4.00-4.09 (2H, m), 3.55-3. 62 (2H, m), 2.79-2. 90 (2H, m), 2.55-2. 67 (4H, m), 1.78-1. 98 (5H, m), 1. 74 (6H, s), 1.44-1. 58 (2H, m)

LCMS: m/z 489 [M+H] +

HPLC retention time: 1.88 min (analysis condition U)

Compound B2-14

8-[4-((2R,6S)-2,6-Dimethyl-morpholin-4-yl)-piperidin-1-yl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound B2-7-2 and (2R,6S)-2,6-dimethylmorpholine.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 60 (1H, s), 8.25-8. 31 (1H, m), 7.97-8. 02 (1H, m), 7. 95 (1H, s), 7.51-7. 58 (1H, m), 7. 18 (1H, s), 6.99-7. 05 (1H, m), 3.96-4. 06 (2H, m), 3.45-3. 55 (2H, m), 2.80-2. 91 (2H, m), 2.72-2. 79 (2H, m), 2.29-2. 41 (1H, m), 1.70-1. 90 (10H, m), 1.40-1. 53 (2H, m), 1. 03 (6H, d, 6.3 Hz)

LCMS: m/z 483 [M+H] +

HPLC retention time: 1.83 min (analysis condition U)

Compound B2-15

8-((3R,5S)-3,5-Dimethylpiperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and 2,6-dimethylpiperazine.

LCMS: m/z 399 [M+H] +

HPLC retention time: 1.76 min (analysis condition U)

Compound B2-16-1

(S)-4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester

Under the same conditions as the method for synthesizing Compound B2-10, the title compound was prepared from Compound B1 and (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester.

LCMS: m/z 485 [M+H] +

HPLC retention time: 3.97 min (analysis condition W)

Compound B2-16-2

6,6-Dimethyl-8-((S)-2-methyl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound 2-16-1.

LCMS: m/z 385 [M+H] +

HPLC retention time: 2.43 min (analysis condition W)

Compound B2-16-3

8-((S)-4-Cyclobutyl-2-methyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound B2-16-2 and cyclobutanone.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8. 31 (1H, d, 8 Hz), 8. 03 (1H, d, 12 Hz), 7. 98 (1H, s), 7. 59 (1H, d, 12 Hz), 7. 13 (1H, s), 6. 98 (1H, d, 8 Hz), 4.35-4. 28 (1H, m), 3. 70 (1H, d, 12 Hz), 3. 02 (1H, ddd, 12, 12, 4 Hz), 2. 87 (1H, d, 8 Hz), 2.74-2. 67 (2H, m), 2. 08-1. 99 (2H, m), 1.92-1. 64 (10H, m), 1.70-1. 62 (2H, m), 1. 12 (3H, d, 8 Hz)

LCMS: m/z 439 [M+H] +

HPLC retention time: 2.59 min (analysis condition W)

Compound B2-17

8-(2-Diethylamino-ethylsulfanyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Trifluoro-methanesulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 25 mg, 0.057 mmol) was dissolved in dimethoxyethane (0.5 mL), added with 2-diethylaminoethanethiol hydrochloric acid salt (19.6 mg, 2 eq.), Pd 2 (dba) 3 (2.6 mg, 0.05 eq.), Xantphos (3.3 mg, 0.1 eq.) and DIPEA (0.06 mg, 6 eq.), and the mixture was stirred at 160° C. for 30 min. The reaction solution was added to water, extracted with ethyl acetate, and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (dichloromethane/methanol) to obtain the target compound (white amorphous, 22.4 mg, 93%).

1 H-NMR (400 MHz, CDCl 3 ) δ: 9. 60 (1H, s), 8.53-8. 48 (1H, m), 8. 32 (1H, d, J=8.4 Hz), 7. 77 (1H, s), 7.53-7. 50 (2H, m), 7.38-7. 35 (1H, m), 3.18-3. 12 (2H, m), 2.81-2. 75 (2H, m), 2.65-2. 57 (4H, m), 1.76 (6H, s), 1. 08-1. 04 (6H, m)

LCMS: m/z 418 [M+H] +

HPLC retention time: 2.10 min (analysis condition U)

Compound B2-18

8-(2-Diisopropylamino-ethylsulfanyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-17, the title compound was prepared from Compound B1 and 2-diisopropylaminoethanethiol hydrochloric acid salt.

LCMS: m/z 446 [M+H] +

HPLC retention time: 2.22 min (analysis condition U)

Compound B2-19

8-(2-Dimethylamino-ethylsulfanyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-17, the title compound was prepared from Compound B1 and 2-dimethylaminoethanethiol hydrochloric acid salt.

LCMS: m/z 390 [M+H] +

HPLC retention time: 1.98 min (analysis condition U)

Compound B2-20

3-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl sulfanyl)-propionic acid

Under the same conditions as the method for synthesizing Compound B2-17, the title compound was prepared from Compound B1 and 3-mercaptopropionic acid.

LCMS: m/z 391 [M+H] +

HPLC retention time: 2.45 min (analysis condition U)

Compound B2-21

8-(2,3-Dihydroxy-propylsulfanyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-17, the title compound was prepared from Compound B1 and 3-mercaptopropane-1,2-diol.

LCMS: m/z 393 [M+H] +

HPLC retention time: 2.15 min (analysis condition U)

Compound B2-22-1

4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

To trifluoro-methanesulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 7.80 g, 18.0 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (6.11 g, 19.8 mmol, 1.1 eq.), Pd(PPh 3 ) 2 Cl 2 (630 mg, 0.898 mmol, 0.05 eq.), and sodium carbonate (5.71 g, 53.9 mmol, 3.0 eq.), DME (125 ml) and water (25 ml) were added. The mixture was subjected to reduced pressure under ultrasonication treatment, followed by flushing with nitrogen gas. This procedure was repeated five times and then degassed. After further stirring at 80° C. for 2 hr under nitrogen atmosphere, the mixture was cooled to room temperature, added with water (250 ml), and further stirred for 30 min. The precipitates were filtered and washed with water (50 ml). They were further washed with CH 3 CN (50 ml) to obtain the target compound as a crude product (gray powder, 7.54 g, 90%).

LCMS: m/z 468 [M+H] +

HPLC retention time: 2.90 min (analysis condition S)

Compound B2-22-2

6,6-Dimethyl-11-oxo-8-(1,2,3,6-tetrahydro-pyridin-4-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound B2-22-1.

LCMS: m/z 368 [M+H] +

HPLC retention time: 1.47 min (analysis condition S)

Compound B2-23

6,6-Dimethyl-8-(1-methyl-1H-pyrazol-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-22-1, the title compound was prepared from Compound B1 and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

LCMS: m/z 367 [M+H] +

HPLC retention time: 2.42 min (analysis condition U)

Compound B2-24

6,6-Dimethyl-11-oxo-8-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under nitrogen atmosphere, trifluoro-methanesulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 1.00 g, 2.302 mmol) was added with n-propanol (20 mL), potassium vinyltrifluoroborate (854 mg, 3.0 eq.), dichloro-((bis-diphenylphosphino)ferrocenyl)palladium (217 mg, 0.1 eq.) and triethylamine (1.11 ml, 3.0 eq.) in order and the resultant was stirred at 60° C. for 4 hr. Upon the completion of the reaction, water was added to the reaction solution. The resulting precipitates were filtered and washed with distilled water, and the residues were dried to obtain the title compound (666 mg, 80%).

1 H-NMR (400 MHz, CDCl 3 ) δ: 8. 90 (1H, s), 8. 55 (1H, d, J=7.9 Hz), 8. 40 (1H, d, J=8.5 Hz), 7. 79 (1H, s), 7.58-7. 61 (3H, m), 6. 85 (1H, dd, J=17.7, 11. 0 Hz), 5. 95 (1H, d, J=17. 1 Hz), 5. 46 (1H, d, J=11. 0 Hz), 1. 84 (6H, s)

LCMS: m/z 313 [M+H] +

HPLC retention time: 3.75 min (analysis condition W)

Compound B2-25-1

4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester

4-Methylene-piperidine-1-carboxylic acid tert-butyl ester (409 mg, 2.07 mmol, 1.2 eq.) was dissolved in THF (2 ml), added under nitrogen atmosphere with 9-BBN (0.5 M THF solution, 4.83 ml, 2.42 mmol, 1.4 eq.) and then stirred at 60° C. for 1 hr. Thereafter, 9-BBN (0.5 M THF solution, 5.52 ml, 2.77 mmol, 1.6 eq.) was further added and the mixture was stirred at 60° C. for 1 hr. The resulting mixture was cooled to room temperature, added with cesium fluoride (1.31 g, 8.60 mmol, 5.0 eq.), and stirred at room temperature for 30 min.

To the solution obtained from the above, DMF (18 ml) suspension comprising trifluoro-methanesulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 750 mg, 1.73 mmol) and dichloro-((bisdiphenylphosphino)ferrocenyl)palladium (70.5 mg, 0.0863 mmol, 0.05 eq.) was added, and the mixture was stirred at 100° C. for 3 hr. After cooling to the room temperature, water (50 ml) was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain 4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl methyl)-piperidine-1-carboxylic acid tert-butyl ester (yellow powder, 763 mg, 91%).

LCMS: m/z 484 [M+H] +

HPLC retention time: 2.97 min (analysis condition S)

Compound B2-25-2

6,6-Dimethyl-11-oxo-8-piperidin-4-ylmethyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound B2-25-1.

LCMS: m/z 384 [M+H] +

HPLC retention time: 1.40 min (analysis condition S)

Compound B2-26-1

Tert-butyl 4-((3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)methyl)piperidin-1-yl sulfonylcarbamic acid

Under the same conditions as the method for synthesizing Compound A9-1, the title compound was prepared from Compound B2-25-2 and N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-yl sulfonyl]azanide (CAS No. 872496-91-8).

LCMS: m/z 563 [M+H] +

HPLC retention time: 2.63 min (analysis condition S)

Compound B2-26-2

4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylmethyl)-piperidine-1-sulfonic acid amide

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound B2-26-1.

LCMS: m/z 463 [M+H] +

HPLC retention time: 2.10 min (analysis condition S)

Compound B2-27

8-(1-Isopropyl-piperidin-4-ylmethyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound B2-25-2 and acetone.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 80 (1H, s), 8. 32 (1H, d, 7.9 Hz), 8. 12 (1H, d, 7.9 Hz), 8. 01 (1H, s), 7. 65 (1H, s), 7. 61 (1H, d, 9.1 Hz), 7. 30 (1H, d, 7. 9 Hz), 2. 75 (2H, d, 11. 0 Hz), 2. 65 (3H, q, 6.5 Hz), 2. 04 (2H, t, 11. 0 Hz), 1. 77 (6H, s), 1. 60-1.57 (3H, m), 1. 22 (2H, t, 11. 6 Hz), 0. 94 (6H, d, 6.7 Hz)

LCMS: m/z 426 [M+H] +

Compound B2-28

3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic acid

Under nitrogen atmosphere, to the dimethyl formamide (3 ml) solution comprising trifluoro-methanesulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 150 mg, 0.345 mmol), lithium formate monohydrate (90 mg, 5.0 eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (20 mg, 0.1 eq.), Pd 2 (dba) 3 (32 mg, 0.1 eq.), lithium chloride (88 mg, 6.0 eq.), N,N-diisopropylethylamine (241 μl, 4.0 eq.), and acetic anhydride (131 μl, 4.0 eq.) were added, and the mixture was stirred at 80° C. for 15 hr. Upon the completion of the reaction, ethyl acetate was added to the reaction solution. The organic layer was washed in order with 1 M hydrochloric acid, distilled water, and brine. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (88 mg, 76%).

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 13. 17 (1H, s), 8. 35 (1H, d, J=7.9 Hz), 8. 34 (1H, s), 8. 23 (1H, d, J=7.9 Hz), 8. 07 (1H, s), 8. 02 (1H, d, J=9.1 Hz), 7. 64 (1H, d, J=7. 9 Hz), 1. 80 (6H, s)

LCMS: m/z 331 [M+H] +

HPLC retention time: 3.08 min (analysis condition W)

Compound B2-29

8-Formyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To the THF (24 ml) and distilled water (6 ml) suspension of 6,6-dimethyl-11-oxo-8-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound B2-24, 600 mg, 1.920 mmol), t-butanol solution of osmium tetraoxide (192 μl, 0.1 eq.) and sodium meta periodate (821 mg, 2.0 eq.) were added and the mixture was stirred at room temperature for 3 hr. Aqueous solution of sodium thiosulfate (0.3 M) was added to the solution, which was then extracted with an ethyl acetate. The organic layer was washed with 10% aqueous solution of disodium ethylenediamine tetraacetic acid. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (470 mg, 77%).

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 95 (1H, s), 10. 20 (1H, s), 8. 48 (1H, s), 8. 42 (1H, d, J=8. 5 Hz), 8. 36 (1H, d, J=8. 5 Hz), 8. 07 (1H, s), 8. 02 (1H, d, J=7. 9 Hz), 7. 67 (1H, d, J=7.9 Hz), 1. 85 (6H, s)

LCMS: m/z 315 [M+H] +

HPLC retention time: 3.38 min (analysis condition W)

Compound B3-1

5,6,6-Trimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A10-1, the title compound was prepared from Compound B2-3.

LCMS: m/z 386 [M+H] +

HPLC retention time: 2.62 min (analysis condition U)

Compound B3-2-1

Tert-butyl 4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperazin-1-yl sulfonylcarbamic acid

Under the same conditions as the method for synthesizing Compound A9-1, the title compound was prepared from Compound B2-5-2 and N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-yl sulfonyl]azanide (CAS No. 872496-91-8).

LCMS: m/z 550 [M+H] +

HPLC retention time: 2.39 min (analysis condition S)

Compound B3-2-2

4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperazine-1-sulfonic acid amide

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound B3-2-1.

LCMS: m/z 450 [M+H] +

HPLC retention time: 1.82 min (analysis condition S)

Compound B3-3

4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperazine-1-sulfonic acid dimethylamide

Under the same conditions as the method for synthesizing Compound A9-1, the title compound was prepared from Compound B2-5-2 and dimethylsulfamoyl chloride.

LCMS: m/z 478 [M+H] +

HPLC retention time: 2.45 min (analysis condition S)

Compound B3-4

4-(3-Cyano-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperazine-1-sulfonic acid dimethylamide

To the DMF suspension of 4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperazine-1-sulfonic acid amide (Compound B3-2-2, 20 mg, 0.04 mmol) and sodium hydride (21.4 mg, 12 eq.), iodomethane (28 μl, 10 eq.) was added and stirred at room temperature overnight. Water was added to the reaction solution, followed by filtration to obtain the target compound (25.8 mg, 100%).

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 43 (1H, d, J=8.2 Hz), 8. 31 (1H, s), 8. 03 (1H, d, J=8. 9 Hz), 7. 64 (1H, dd, J=8. 1, 1. 3 Hz), 7. 30 (1H, d, J=2. 0 Hz), 7. 08 (1H, dd, J=8.9, 2.0 Hz), 4. 16 (3H, s), 3.43-3. 53 (4H, t, J=4.7 Hz), 3.26-3. 41 (4H, s), 2. 82 (6H, s), 1. 87 (6H, s).

LCMS: m/z 492 [M+H] +

HPLC retention time: 2.69 min (analysis condition S)

Compound B3-5

8-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

The title compound was obtained as a by-product of the synthesis of Compound F5-36.

LCMS: m/z 411 [M+H] +

HPLC retention time: 1.31 min (analysis condition S)

Compound B3-6

8-(4-Cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound B2-5-2 and cyclobutanone.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8. 29 (1H, d, J=8.2 Hz), 8. 01 (1H, d, J=8.8 Hz), 7. 96 (1H, s), 7. 55 (1H, d, J=8.2 Hz), 7. 19 (1H, d, J=2.2 Hz), 7. 03 (1H, dd, J=2.4, 8.8 Hz), 2.71-2. 75 (1H, m), 2.37-2. 39 (4H, m), 1.98-2. 00 (2H, m), 1.77-1. 85 (2H, m), 1.74 (6H, s), 1.63-1. 68 (2H, m).

LCMS: m/z 425 [M+H] +

HPLC retention time: 1.80 min (analysis condition U)

Compound B3-7

6,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound B2-5-2 and 3-oxetanone.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8. 29 (1H, dd, J=8.2, 0.59 Hz), 8. 02 (1H, d, J=9.0 Hz), 7. 97 (1H, d, J=0. 59 Hz), 7. 56 (1H, dd, J=8.0, 1.4 Hz), 7.22 (1H, d, J=2.3 Hz), 7. 04 (1H, dd, J=8.8, 2.2 Hz), 4.56-4. 59 (2H, m), 4.47-4. 50 (2H, m), 3. 43-3. 48 (1H, m), 3.39-3. 42 (4H, m), 2.40-2. 42 (4H, m), 1. 74 (6H, s)

LCMS: m/z 427 [M+H] +

HPLC retention time: 1.67 min (analysis condition U)

Compound B3-8

8-(2-Diethylamino-ethanesulfonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

8-(2-Diethylamino-ethylsulfanyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound B2-17, 16.8 mg, 0.0402 mmol) was dissolved in methanol (1.5 mL), added with oxone (54.3 mg, 2.2 eq.) which had been dissolved in water (0.5 mL), and then stirred at room temperature for 2 hr. The reaction solution was concentrated, extracted with ethyl acetate, washed with saturated sodium hydrogen carbonate, and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (dichloromethane/methanol) to obtain the target compound (white solid, 5.8 mg, 32%).

1 H-NMR (400 MHz, CDCl 3 ) δ: 9. 29 (1H, s), 8. 61 (1H, d, J=8.2 Hz), 8. 52 (1H, d, J=8.0 Hz), 8. 21 (1H, s), 8. 01 (1H, d, J=8.2 Hz), 7. 81 (1H, s), 7. 61 (1H, d, J=8. 2 Hz), 3. 33 (2H, t, J=7. 4 Hz), 2. 95 (2H, t, J=7. 4 Hz), 2. 41 (4H, q, J=7. 2 Hz), 1. 86 (6H, s), 0.89 (4H, t, J=7.1 Hz)

LCMS: m/z 450 [M+H] +

HPLC retention time: 2.05 min (analysis condition U)

Compound B3-9

8-(2-Diisopropylamino-ethanesulfonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-8, the title compound was prepared from Compound B2-18.

LCMS: m/z 478 [M+H] +

HPLC retention time: 2.18 min (analysis condition U)

Compound B3-10

8-(2-Dimethylamino-ethanesulfonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-8, the title compound was prepared from Compound B2-19.

LCMS: m/z 422 [M+H] +

HPLC retention time: 2.03 min (analysis condition U)

Compound B3-11

3-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-sulfonyl)-propionic acid

Under the same conditions as the method for synthesizing Compound B3-8, the title compound was prepared from Compound B2-20.

LCMS: m/z 423 [M+H] +

HPLC retention time: 2.28 min (analysis condition U)

Compound B3-12

8-(2,3-Dihydroxy-propane-1-sulfonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-8, the title compound was prepared from Compound B2-21.

LCMS: m/z 425 [M+H] +

HPLC retention time: 2.17 min (analysis condition U)

Compound B3-13-1

4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidine-1-carboxylic acid tert-butyl ester

4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Compound B2-22-1, 16.2 g, 34.6 mmol) was dissolved in THF (800 ml) and methanol (230 ml), added with 10 wt % Pd/C (3.2 g), and stirred under hydrogen atmosphere for 19 hr. The solid was filtered through Celite, eluted with a mixture solvent (400 ml; THF/methanol=4/1), and concentrated under reduced pressure. The residues were dissolved in ethyl acetate (400 ml), and then washed with 1% aqueous solution of N-acetylcysteine, saturated aqueous solution of NaHCO 3 and saturated brine. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues were concentrated under reduced pressure to obtain the title compound as a crude product (white powder, 14.0 g, 86%).

LCMS: m/z 470 [M+H] +

HPLC retention time: 2.88 min (analysis condition S)

Compound B3-13-2

6,6-Dimethyl-11-oxo-8-piperidin-4-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound B3-13-1.

LCMS: m/z 370 [M+H] +

HPLC retention time: 1.30 min (analysis condition S)

Compound B3-14

8-(1,2-Dihydroxy-ethyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To the THF (1 ml) solution of 6,6-dimethyl-11-oxo-8-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound B2-24, 20 mg, 0.064 mmol), t-butanol solution of osmium tetraoxide (19 μl, 0.3 eq.) and 50% aqueous solution of N-methylmorpholine-N-oxide (30 μl, 2.0 eq.) were added and the mixture was stirred at room temperature for 3 hr. To the reaction solution, 10% aqueous solution of disodium ethylenediamine tetraacetic acid was added, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by high performance liquid chromatography to obtain the title compound (21 mg, 63%).

1 H-NMR (400 MHz, CD 3 OD) δ: 8. 41 (1H, d, J=7.9 Hz), 8. 29 (1H, d, J=7. 9 Hz), 7.87 (1H, s), 7. 86 (1H, s), 7. 57 (1H, d, J=7.9 Hz), 7. 52 (1H, d, J=6.7 Hz), 4.85 (1H, dd, J=7.0, 4.6 Hz), 3. 73 (1H, dd, J=11.3, 4.6 Hz), 3. 68 (1H, dd, J=11.3, 7.0 Hz), 1. 83 (6H, s)

LCMS: m/z 347 [M+H] +

HPLC retention time: 2.68 min (analysis condition W)

Compound B3-15

6,6-Dimethyl-8-(morpholine-4-carbonyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To the tetrahydrofuran (1 ml) solution of 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic acid (Compound B2-28, 15 mg, 0.045 mmol), morpholine (6 μl, 1.5 eq.), hexafluorophosphoric acid uronium 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylmethane aminium (HATU) (26 mg, 1.5 eq.), and N,N-diisopropylethylamine (24 μl, 3.0 eq.) were added and the mixture was stirred at room temperature for 3 hr. The reaction solution was filtered to remove insoluble matters and the residues obtained after concentration under reduced pressure were purified by high performance liquid chromatography to obtain the title compound (11 mg, 55%).

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 85 (1H, s), 8. 33 (1H, d, J=8.5 Hz), 8. 27 (1H, d, J=7.9 Hz), 8. 03 (1H, s), 7. 92 (1H, s), 7. 63 (1H, d, J=8.5 Hz), 7. 54 (1H, d, J=7.9 Hz), 3.52-3. 77 (6H, m), 3.30-3. 42 (2H, m), 1.79 (6H, s)

LCMS: m/z 400 [M+H] +

HPLC retention time: 2.96 min (analysis condition W)

Compound B3-16

8-(4-Methanesulfonyl-piperazin-1-carbonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 1-methanesulfonylpiperazine.

LCMS: m/z 477 [M+H] +

HPLC retention time: 3.03 min (analysis condition W)

Compound B3-17

8-(4-Hydroxy-piperidin-1-carbonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and piperidin-4-ol.

LCMS: m/z 414 [M+H] +

HPLC retention time: 2.75 min (analysis condition W)

Compound B3-18

3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide

Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 2-aminopropane-1,3-diol.

LCMS: m/z 404 [M+H] +

HPLC retention time: 2.60 min (analysis condition W)

Compound B3-19

3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic acid (2-methanesulfonyl-ethyl)-amide

Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 2-methanesulfonylethylamine.

LCMS: m/z 436 [M+H] +

HPLC retention time: 2.87 min (analysis condition W)

Compound B3-20

3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic acid (1,1-dioxo-tetrahydro-thiophen-3-yl)-amide

Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and (1,1-dioxotetrahydrothiophen-3-yl)amine

LCMS: m/z 448 [M+H] +

HPLC retention time: 1.70 min (analysis condition S)

Compound B3-21

3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic acid ((R)-2,3-dihydroxy-propyl)-amide

Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and (R)-(+)-3-amino-1,2-propanediol.

LCMS: m/z 404 [M+H] +

HPLC retention time: 1.38 min (analysis condition S)

Compound B3-22

3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic acid bis-(2-hydroxy-ethyl)-amide

Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and N,N-diethanolamine.

LCMS: m/z 418 [M+H] +

HPLC retention time: 1.35 min (analysis condition S)

Compound B3-23

3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic acid oxetan-3-yl amide

Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and oxetan-3-yl amine.

LCMS: m/z 386 [M+H] +

HPLC retention time: 1.63 min (analysis condition S)

Compound B3-24

3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic acid (2-hydroxy-ethoxy)-amide

Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 2-aminooxy-ethanol.

LCMS: m/z 390 [M+H] +

HPLC retention time: 1.54 min (analysis condition S)

Compound B3-25-1

2-[(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carbonyl)-amino]-ethyl}-carbamic acid tert-butyl ester

Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and (2-amino-ethyl)-carbamic acid tert-butyl ester.

LCMS: m/z 473 [M+H] +

HPLC retention time: 2.08 min (analysis condition S)

Compound B3-25-2

3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic acid (2-amino-ethyl)-amide

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound B3-25-1.

LCMS: m/z 373 [M+H] +

HPLC retention time: 1.19 min (analysis condition S)

Compound B3-25-3

3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic acid (2-methanesulfonylamino-ethyl)-amide

Under the same conditions as the method for synthesizing Compound A9-1, the title compound was prepared from Compound B3-25-2.

LCMS: m/z 451 [M+H] +

HPLC retention time: 1.62 min (analysis condition S)

Compound B3-26

3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic acid (2-hydroxy-ethyl)-methyl-amide

Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 2-methylamino-ethanol.

LCMS: m/z 388 [M+H] +

HPLC retention time: 1.53 min (analysis condition S)

Compound B3-27-1

Tert-butyl N-(2-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxamide)ethyl)sulfamoylcarbamic acid

Under the same conditions as the method for synthesizing Compound A9-1, the title compound was prepared from Compound B3-25-2 and N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-yl sulfonyl]azanide (CAS No. 872496-91-8).

LCMS: m/z 552 [M+H] +

HPLC retention time: 2.03 min (analysis condition S)

Compound B3-27-2

3-Cyano-6,6-dimethyl-11-oxo-N-(2-(sulfamoylamino)ethyl)-6,11-dihydro-5H-benzo[b]carbazol-8-carboxamide

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound B3-27-1.

LCMS: m/z 452 [M+H] +

HPLC retention time: 1.57 min (analysis condition S)

Compound B3-28

8-[4-(2-Hydroxy-ethyl)-piperazin-1-carbonyl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 2-piperazin-1-yl ethanol.

LCMS: m/z 443 [M+H] +

HPLC retention time: 1.75 min (analysis condition U)

Compound B3-29

8-(4-Tert-butyl-piperazin-1-carbonyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 1-tert-butylpiperazine.

LCMS: m/z 455 [M+H] +

HPLC retention time: 1.88 min (analysis condition U)

Compound B3-30

8-[4-(2-Methoxy-ethyl)-piperazin-1-carbonyl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 1-(2-methoxyethyl)piperazine.

LCMS: m/z 457 [M+H] +

HPLC retention time: 1.83 min (analysis condition U)

Compound B3-31-1

4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester

Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and piperazine-1-carboxylic acid tert-butyl ester.

LCMS: m/z 499 [M+H] +

HPLC retention time: 2.63 min (analysis condition U)

Compound B3-31-2

6,6-Dimethyl-11-oxo-8-(piperazin-1-carbonyl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound B3-31-1.

LCMS: m/z 399 [M+H] +

HPLC retention time: 1.78 min (analysis condition U)

Compound B3-32

6,6-Dimethyl-8-morpholin-4-yl methyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To the THF (1 ml) solution of Compound B2-29 (30 mg, 0.095 mmol), morpholine (6 μl, 1.5 eq.) and sodium triacetoxyborohydride (81 mg, 2.0 eq.) were added and stirred at room temperature for 1 hr. The reaction solution was filtered to remove insoluble matters, and the residues obtained after concentration under reduced pressure were purified by high performance liquid chromatography to obtain the title compound (19 mg, 50%).

1 H-NMR (400 MHz, CD 3 OD) δ: 8. 41 (1H, d, 7.9 Hz), 8. 27 (1H, d, 8.5 Hz), 7. 87 (1 s), 7. 81 (1H, s), 7. 56 (1H, d, 8.5 Hz), 7. 49 (1H, d, 7. 9 Hz), 3. 71 (4H, t, 4.6 Hz), 3. 68 (2H, s), 2. 51 (4H, t, 4.6 Hz), 1. 82 (6H, s)

LCMS: m/z 386 [M+H] +

HPLC retention time: 2.41 min (analysis condition W)

Compound B3-33

6,6-Dimethyl-8-(4-methyl-piperazin-1-yl methyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound B2-29 and 1-methylpiperazine.

1 H-NMR (400 MHz, CD 3 OD) δ: 8. 41 (1H, d, 7.9 Hz), 8. 26 (1H, d, 7.9 Hz), 7. 88 (1 s), 7. 81 (1H, s), 7. 56 (1H, d, 7.9 Hz), 7. 48 (1H, d, 7.9 Hz), 3. 70 (2H, s), 2.42-2. 78 (8H, m), 2. 31 (3H, s), 1. 82 (6H, s)

LCMS: m/z 399 [M+H] +

HPLC retention time: 2.30 min (analysis condition W)

Compound B3-34

8-[4-(1,1-Dioxide-4-thiomorpholinyl)methyl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound B2-29 and thiomorpholine 1,1-dioxide.

LCMS: m/z 434 [M+H] +

HPLC retention time: 2.75 min (analysis condition W)

Compound B3-35

8-(4-Methanesulfonyl-piperazin-1-ylmethyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound B2-29 and 1-methanesulfonylpiperazine.

1 H-NMR (400 MHz, CD 3 OD) δ: 8. 41 (1H, d, 8.5 Hz), 8. 28 (1H, d, 7.9 Hz), 7. 87 (1 s), 7. 80 (1H, s), 7. 56 (1H, d, 8.5 Hz), 7. 50 (1H, d, 7.9 Hz), 3. 73 (2H, s), 3.24-3. 28 (4H, m), 2. 85 (3H, s), 2.59-2. 65 (4H, m), 1. 82 (6H, s)

LCMS: m/z 463 [M+H] +

HPLC retention time: 2.47 min (analysis condition W)

Compound B3-36

4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-ylmethyl)-piperazine-1-sulfonic acid dimethylamide

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound B2-29 and piperazine-1-sulfonic acid dimethylamide.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 79 (1H, s), 8. 32 (1H, d, 7.9 Hz), 8. 18 (1H, d, 7.9 Hz), 8. 00 (1 s), 7. 77 (1H, s), 7. 60 (1H, d, 7.9 Hz), 7. 46 (1H, d, 7.9 Hz), 3. 67 (2H, s), 3.18-3. 23 (4H, m), 2. 76 (6H, s), 2.45-2. 50 (4H, m), 1. 77 (6H, s)

LCMS: m/z 492 [M+H] +

HPLC retention time: 2.58 min (analysis condition W)

Compound B3-37

6,6-Dimethyl-11-oxo-8-[(2,2,2-trifluoro-ethylamino)-methyl]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound B2-29 and 2,2,2-trifluoroethylamine.

LCMS: m/z 398 [M+H] +

HPLC retention time: 2.73 min (analysis condition W)

Compound B3-38

8-Hydroxymethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

The by-product obtained from the synthesis of Compound B3-37 was purified by high performance liquid chromatography to obtain the target compound.

LCMS: m/z 317 [M+H] +

HPLC retention time: 2.91 min (analysis condition W)

Compound B4-1

8-(1-Cyclobutyl-piperidin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound B3-13-2 and cyclobutanone.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 73 (1H, s), 8.28-8. 33 (1H, m), 8.09-8. 14 (1H, m), 7. 99 (1H, s), 7. 72 (1H, s), 7.56-7. 62 (1H, m), 7.34-7. 41 (1H, m), 3.52-3. 64 (2H, m), 2.85-2. 95 (2H, m), 2.56-2. 75 (2H, m), 1.91-2. 04 (2H, m), 1.56-1. 84 (14H, m)

LCMS: m/z 424 [M+H] +

HPLC retention time: 1.87 min (analysis condition U)

Compound B4-2

8-(1-Methanesulfonyl-piperidin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A9-1, the title compound was prepared from Compound B3-13-2 and mesyl chloride.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 77 (1H, s), 8. 31 (1H, d, 8.6 Hz), 8. 15 (1H, d, 8.2 Hz), 8. 00 (1H, s), 7. 77 (1H, s), 7. 59 (1H, d, 7.3 Hz), 7. 42 (1H, d, 8.6 Hz), 3.74-3. 70 (1H, m), 2. 93 (3H, s), 2.86-2. 77 (4H, m), 1.93-1. 87 (4H, m), 1. 77 (6. 0H, s)

LCMS: m/z 448 [M+H] +

HPLC retention time: 2.37 min (analysis condition S)

Compound B4-3-1

Tert-butyl-4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)piperidin-1-yl sulfonylcarbamic acid

Under the same conditions as the method for synthesizing Compound A9-1, the title compound was prepared from Compound B3-13-2 and N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridine-1-yl-sulfonyl]azanide.

LCMS: m/z 549 [M+H] +

HPLC retention time: 2.72 min (analysis condition S)

Compound B4-3-2

4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidine-1-sulfonic acid amide

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound B4-3-1.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 78 (1H, s), 8. 29 (1H, d, 7.9 Hz), 8. 14 (1H, d, 8. 5 Hz), 7. 97 (1H, s), 7. 76 (1H, s), 7. 55 (1H, d, 8. 5 Hz), 7. 41 (1H, d, 7. 9 Hz), 6. 79 (2H, s), 3. 63 (2H, d, 12. 2 Hz), 2.80-2.73 (1H, m), 2.70-2. 64 (2H, m), 1. 96-1. 93 (2H, m), 1.87-1. 81 (2H, m), 1. 77 (6H, s)

LCMS: m/z 449 [M+H] +

HPLC retention time: 2.03 min (analysis condition S)

Compound B4-4

4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidine-1-sulfonic acid methylamide

Under the same conditions as the method for synthesizing Compound A9-1, the title compound was prepared from Compound B3-13-2 and 2-oxooxazolidine-3-sulfonic acid methylamide.

LCMS: m/z 463 [M+H] +

HPLC retention time: 2.40 min (analysis condition S)

Compound B4-5

4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidine-1-sulfonic acid dimethylamide

Under the same conditions as the method for synthesizing Compound A9-1, the title compound was prepared from Compound B3-13-2 and dimethylsulfamoyl chloride.

LCMS: m/z 477 [M+H] +

HPLC retention time: 2.65 min (analysis condition S)

Compound B4-6

6,6-Dimethyl-8-(1-methyl-piperidin-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A9-1, the title compound was prepared from Compound B3-13-2 and iodomethane.

LCMS: m/z 384 [M+H] +

HPLC retention time: 1.50 min (analysis condition S)

Compound B4-7

8-(1-Isopropyl-piperidin-4-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound B3-13-2 and acetone.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 77 (1H, s), 8. 32 (1H, d, 7.9 Hz), 8. 13 (1H, d, 7.9 Hz), 8. 01 (1H, s), 7. 73 (1H, s), 7. 61 (1H, d, 9.1 Hz), 7. 39 (1H, d, 9.8 Hz), 2. 93 (2H, d, 11. 0 Hz), 2.77-2. 71 (1H, m), 2.67-2. 62 (1H, m), 2. 25 (2H, t, 10. 1 Hz), 1.80-1. 73 (10H, m), 1. 02 (6H, d, 6.7 Hz)

LCMS: m/z 412 [M+H] +

HPLC retention time: 1.60 min (analysis condition S)

Compound B4-8

6,6-Dimethyl-8-(1-oxetan-3-yl-piperidin-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound B3-13-2 and oxetan-3-one.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 74 (1H, s), 8. 32 (1H, d, 7.9 Hz), 8. 13 (1H, d, 7.9 Hz), 8. 00 (1H, s), 7. 74 (1H, s), 7. 61 (1H, d, 9.8 Hz), 7. 40 (1H, d, 7.9 Hz), 4. 56 (2H, t, 6.7 Hz), 4. 46 (2H, t, 6.1 Hz), 3.46-3. 39 (1H, m), 2.85-2. 82 (2H, m), 2. 71-2. 64 (1H, m), 1.92-1. 86 (2H, m), 1.82-1. 79 (4H, m), 1. 77 (6H, s)

LCMS: m/z 426 [M+H] +

HPLC retention time: 1.53 min (analysis condition S)

Sulfuric Acid Salt of Compound B4-8

6,6-Dimethyl-8-(1-oxetan-3-yl-piperidin-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile was dissolved at 80° C. in a mixture of 5 volumes of DMA and 1.4 volumes of 2 N sulfuric acid. After cooling to room temperature, 15 volumes of acetone were added dropwise, and the precipitated solids were filtered and dried to obtain sulfuric acid salt of 6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 81 (1H, s), 10. 26 (1H, br. s), 8. 33 (1H, d, 8. 3 Hz), 8. 21 (1H, d, 8. 3 Hz), 8. 04 (1H, s), 7. 75 (1H, s), 7. 63 (1H, d, 8. 3 Hz), 7. 41 (1H, d, 8.3 Hz), 4.85-4. 70 (4H, m), 4.50-4. 40 (1H, br. s), 3.60-3. 00 (6H, br. m), 2. 20-2. 10 (2H, m), 2.05-1. 90 (2H, m), 1. 79 (6H, s)

LCMS: m/z 426 [M+H] +

Compound B4-9

4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidine-1-carboxylic acid ethylamide

Under the same conditions as the method for synthesizing Compound A9-1, the title compound was prepared from Compound B-3-13-2 and ethylisocyanate.

LCMS: m/z 441 [M+H] +

HPLC retention time: 2.20 min (analysis condition S)

Compound B4-10

8-[1-(Imidazole-1-sulfonyl)-piperidin-4-yl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

According to the method disclosed in Journal of Organic Chemistry, 2003, page 115, 6,6-dimethyl-11-oxo-8-piperidin-4-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound B3-13-2, 10 mg, 0.027 mmol) was reacted with 3-(imidazole-1-sulfonyl)-1-methyl-3H-imidazol-1-ium (19 mg, 2 eq.). After removing the solvent, the residues were purified by liquid chromatography to obtain the title compound (3 mg).

LCMS: m/z 500 [M+H] +

HPLC retention time: 2.80 min (analysis condition C)

Compound CC1

3-Methoxy-5,5-dimethyl-6-oxo-5,6,7,8-tetrahydro-naphthalen-2-sulfonyl chloride

To the dichloromethane (2 ml) solution of 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 200 mg, 0.980 mmol), chlorosulfonic acid (110 μl, 1.70 eq.) was added and the mixture was stirred at room temperature for 2 hr. To the reaction solution, oxalyl chloride (297 μl, 3.0 eq.) and N,N-dimethyl formamide (45 μl, 0.6 eq.) were added in three divided portions, and the mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure to obtain the title compound (295 mg). Since the title compound is unstable, its structure was identified in the next step.

Compound CC2-1

7-Methoxy-1,1-dimethyl-6-(pyrrolidine-1-sulfonyl)-3,4-dihydro-1H-naphthalen-2-one

The THF (4 ml) solution of 3-methoxy-5,5-dimethyl-6-oxo-5,6,7,8-tetrahydro-naphthalen-2-sulfonyl chloride (Compound CC1, 295 mg, 0.974 mmol) was cooled to 0° C., and the tetrafuran (1 ml) solution combining pyrrolidine (121 μl, 1.5 eq.) and triethylamine (272 μl, 2 eq.) was added dropwise thereto over 2 min. The mixture was stirred at 0° C. until Compound CC-1 disappears. The reaction solution was added with distilled water and extracted with ethyl acetate. The organic layer was washed with 10% aqueous solution of disodium ethylenediamine tetraacetic acid. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (246 mg, 75%).

1 H-NMR (400 MHz, CDCl 3 ) δ: 7. 76 (1H, s), 6. 93 (1H, s), 3. 95 (3H, s), 3. 37-3. 46 (4H, m), 3. 09 (0.0H, t, J=6.9 Hz), 2. 69 (0.0H, t, J=6.9 Hz), 1. 82-1. 91 (4H, m), 1.47 (6H, s)

LCMS: m/z 338 [M+H] +

HPLC retention time: 3.21 min (analysis condition W)

Compound CC2-2

7-Methoxy-1,1-dimethyl-6-(4-methyl-piperazine-1-sulfonyl)-3,4-dihydro-1H-naphthalen-2-one

Under the same conditions as the method for synthesizing Compound CC2-1, the title compound was prepared from Compound CC1 and N-methylpiperazine.

LCMS: m/z 367 [M+H] +

HPLC retention time: 2.22 min (analysis condition Y)

Compound CC3-1

8-Methoxy-6,6-dimethyl-9-(pyrrolidine-1-sulfonyl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E2-1, the title compound was prepared from Compound CC2-1.

LCMS: m/z 436 [M+H] +

HPLC retention time: 3.76 min (analysis condition W)

Compound CC3-2

3-Bromo-8-methoxy-6,6-dimethyl-9-(4-methyl-piperazine-1-sulfonyl)-6,11-dihydro-5H-benzo[b]carbazole

Under the same conditions as the method for synthesizing Compound A3-1, the title compound was prepared from Compound CC2-2.

LCMS: m/z 519 [M+H] +

HPLC retention time: 2.99 min (analysis condition Y)

Compound CC4-1

8-Methoxy-6,6-dimethyl-11-oxo-9-(pyrrolidine-1-sulfonyl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A4, the title compound was prepared from Compound CC3-1.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 86 (1H, s), 8. 60 (1H, s), 8. 30 (1H, d, J=8.5 Hz), 8. 01 (1H, s), 7. 60 (1H, s), 7. 59 (1H, d, J=8.5 Hz), 4. 09 (3H, s), 3.21-3. 42 (4H, m), 1. 72-1. 90 (10H, m)

LCMS: m/z 450 [M+H] +

HPLC retention time: 3.40 min (analysis condition W)

Compound CC4-2

3-Bromo-8-methoxy-6,6-dimethyl-9-(4-methyl-piperazine-1-sulfonyl)-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A4, the title compound was prepared from Compound CC3-2.

LCMS: m/z 532, 534 [M+H] +

HPLC retention time: 2.18 min (analysis condition U)

Compound CC-4-3

8-Methoxy-6,6-dimethyl-9-(4-methyl-piperazine-1-sulfonyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A5-2, the title compound was prepared from Compound CC4-2.

LCMS: m/z 479 [M+H] +

HPLC retention time: 1.93 min (analysis condition U)

Compound C1-1

Dimethyl-sulfamic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester

8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A6, 50 mg, 0.165 mmol) was dissolved in DMF (1.5 mL), added with sodium hydride (13 mg, 2.0 eq.) and dimethylsulfamoyl chloride (0.02 mL, 1.2 eq.), and then stirred at room temperature for 1 hr. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues were concentrated under reduced pressure to obtain the target compound (yellowish white powder, 62 mg, 92%).

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 87 (1H, s), 8.40-8. 30 (2H, m), 8. 05 (1H, s), 7. 82 (1H, d, J=1.8 Hz), 7. 64 (1H, d, J=7. 9 Hz), 7. 50 (1H, dd, J=8. 5, 2. 4 Hz), 2.96 (6H, s), 1. 81 (6H, s)

LCMS: m/z 410 [M+H] +

HPLC retention time: 2.38 min (analysis condition S)

Compound C1-2

Morpholine-4-sulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester

According to the same method as the method for synthesizing Compound A8-17, the title compound was prepared as a crude product from Compound A6 and Compound A8-18-0.

Compound C1-4

4-Methyl-piperazine-1-sulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester

According to the same method as the method for synthesizing Compound A8-17, the title compound was prepared as a crude product from Compound A6 and Compound A8-19-0.

Compound C2-1

3-Cyano-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonic acid dimethylamide

To dimethyl-sulfamic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound C1-1, 250 mg, 0.610 mmol), aluminum chloride (1.0 M, nitromethane solution (1.8 mL, 3.0 eq.)) was added and the mixture was stirred at 160° C. for 10 min under irradiation with microwave. Water was added to the reaction solution, which was then extracted with dichloromethane. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (dichloromethane/methanol) to obtain the target compound (yellowish white powder, 99 mg, 40%).

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 78 (1H, s), 11. 72 (1H, s), 8. 50 (1H, s), 8. 32 (1H, d, J=8.5 Hz), 8. 02 (1H, s), 7. 62 (1H, d, J=7.9 Hz), 7. 25 (1H, s), 2. 80 (6H, s), 1.75 (6H, s).

LCMS: m/z 410 [M+H] +

HPLC retention time: 2.00 min (analysis condition S)

Compound C2-2

8-Hydroxy-6,6-dimethyl-11-oxo-9-(pyrrolidine-1-sulfonyl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E3-2, the title compound was prepared from Compound CC4-1.

LCMS: m/z 436 [M+H] +

HPLC retention time: 3.32 min (analysis condition W)

Compound C2-3

8-Hydroxy-6,6-dimethyl-9-(morpholine-4-sulfonyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound C2-1, the title compound was prepared from Compound C1-2.

LCMS: m/z 452 [M+H] +

HPLC retention time: 1.89 min (analysis condition S)

Compound C2-4

8-Hydroxy-6,6-dimethyl-9-(4-methyl-piperazine-1-sulfonyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E3-2, the title compound was prepared from Compound CC4-3.

LCMS: m/z 465 [M+H] +

HPLC retention time: 1.87 min (analysis condition U)

Compound C3-1

Trifluoro-methanesulfonic acid 3-cyano-9-dimethylsulfamoyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester

Under the same conditions as the method for synthesizing Compound B1, the title compound was prepared from Compound C2-1.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 13. 05 (1H, s), 8. 67 (1H, s), 8. 32 (1H, d, J=8.2 Hz), 8. 06 (2H, m), 7. 67 (1H, dd, J=7.9, 1.3 Hz), 2. 79 (6H, s), 1. 84 (6H, s).

LCMS: m/z 542 [M+H] +

HPLC retention time: 2.67 min (analysis condition S)

Compound C3-2

Trifluoro-methanesulfonic acid 3-cyano-6,6-dimethyl-11-oxo-9-(pyrrolidine-1-sulfonyl)-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester

Under the same conditions as the method for synthesizing Compound B1, the title compound was prepared from Compound C2-2.

LCMS: m/z 568 [M+H] +

HPLC retention time: 4.00 min (analysis condition W)

Compound C4-1

3-Cyano-8-(2-methoxy-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonic acid dimethylamide

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound C2-1 and 1-bromo-2-methoxy-ethane.

1 H-NMR (300 MHz, DMSO-d 6 ) σppm; 12. 8 (s, 1H), 8. 58 (s, 1H), 8. 31 (d, 1H, J=8.4 Hz), 8. 03 (s, 1H), 7. 62 (m, 2H), 4. 47 (m, 2H), 3. 75 (m, 2H), 3. 32 (s, 3H), 2. 27 (s, 6H), 1. 83 (s, 6H)

LCMS: m/z 468 [M+H] +

HPLC retention time: 2.68 min (analysis condition U)

Compound C4-2

3-Cyano-8-(2-diethylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonic acid dimethylamide

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound C2-1.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 57 (1H, s), 8. 29 (1H, d, J=8.4 Hz), 8. 02 (1H, s), 7.70-7. 60 (2H, m), 4. 37 (2H, t, J=6.3 Hz), 2. 84 (2H, m), 2. 80 (6H, s), 2. 64-2. 53 (4H, m), 1. 83 (6H, s), 0.98 (6H, t, J=7.1 Hz).

LCMS: m/z 509 [M+H] +

HPLC retention time: 1.55 min (analysis condition S)

Compound C4-3

3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonic acid dimethylamide

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound C2-1 and iodomethane.

LCMS: m/z 424 [M+H] +

HPLC retention time: 2.17 min (analysis condition S)

Compound C4-4

3-Cyano-6,6-dimethyl-11-oxo-8-(piperidin-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonic acid dimethylamide

Under the same conditions as the method for synthesizing Compound A7-1 and Compound A8-1, the title compound was prepared from Compound C2-1 and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.

LCMS: m/z 493 [M+H] +

HPLC retention time: 1.49 min (analysis condition S)

Compound C4-5

3-Cyano-6,6-dimethyl-8-(2-morpholin-4-yl-ethoxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonic acid dimethylamide

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound C2-1 and 2-morpholin-4-yl-ethanol.

LCMS: m/z 523 [M+H] +

HPLC retention time: 1.64 min (analysis condition S)

Compound C4-6

3-Cyano-8-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethoxy]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonic acid dimethylamide

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound C2-1 and 2-(1,1-dioxothiomorpholino)ethanol.

LCMS: m/z 571 [M+H] +

HPLC retention time: 1.75 min (analysis condition S)

Compound C4-7

3-Cyano-8-(1-ethyl-piperidin-4-yl oxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonic acid dimethylamide

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound C2-1 and 1-ethyl-piperidin-4-ol.

LCMS: m/z 521 [M+H] +

HPLC retention time: 1.52 min (analysis condition S)

Compound C4-8

3-Cyano-8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonic acid dimethylamide

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound C3-1.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 61 (1H, s), 8. 30 (1H, d, J=8.1 Hz), 8. 04 (1H, s), 7. 87 (1H, s), 7. 62 (1H, dd, J=8.2, 1.8 Hz), 3.17-3. 06 (2H, m), 2.75-2. 70 (6H, s), 2.67-2. 58 (2H, m), 1. 81 (6H, s), 1. 02 (6H, d, J=6.4 Hz).

LCMS: m/z 520 [M+H] +

HPLC retention time: 1.52 min (analysis condition S)

Compound C4-9

3-Cyano-8-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonic acid dimethylamide

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound C3-1 and 2-piperazin-1-yl-ethanol.

LCMS: m/z 522 [M+H] +

HPLC retention time: 1.40 min (analysis condition S)

Compound C4-10

3-Cyano-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonic acid dimethylamide

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound C3-1 and morpholine.

LCMS: m/z 479 [M+H] +

HPLC retention time: 2.22 min (analysis condition S)

Compound C4-11

4-(3-Cyano-9-dimethylsulfamoyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperazine-1-carboxylic acid tert-butyl ester

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound C3-1 and piperazine-1-carboxylic acid tert-butyl ester.

LCMS: m/z 578 [M+H] +

HPLC retention time: 2.72 min (analysis condition S)

Compound C4-12

3-Cyano-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonic acid dimethylamide

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from C4-11.

1 H-NMR (270 MHz, CD 3 OD) δ: 8. 78 (1H, s), 8. 39 (1H, dd, J=8.2, 0.7 Hz), 7. 88 (1H, m), 7. 75 (1. 1H, s), 7. 55 (1H, dd, J=8.2, 1.5 Hz), 3. 15 (4H, m), 3. 04 (4H, m), 2. 82 (s, 6H), 1. 85 (6H, s)

LCMS: m/z 478 [M+H] +

HPLC retention time: 1.43 min (analysis condition S)

Compound C4-13

6,6-Dimethyl-11-oxo-9-(pyrrolidine-1-sulfonyl)-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound C3-2 and 4-(1-pyrrolidyl)-piperidine.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 83 (1H, s), 8. 64 (1H, s), 8. 32 (1H, d, 8. 2 Hz), 8. 03 (1H, s), 7. 80 (1H, s), 7. 63 (1H, d, 8.2 Hz), 2.87-2. 94 (4H, m), 1.94-1. 99 (4H, m), 1.80 (6H, s), 1. 58-1. 76 (10H, m)

LCMS: m/z 572 [M+H] +

HPLC retention time: 2.81 min (analysis condition W)

Compound C4-14

8-(2-Diethylamino-ethoxy)-6,6-dimethyl-9-(morpholine-4-sulfonyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound C2-3.

LCMS: m/z 551 [M+H] +

HPLC retention time: 1.46 min (analysis condition S)

Compound C4-15

6,6-Dimethyl-9-(morpholine-4-sulfonyl)-11-oxo-8-(tetrahydro-pyran-4-yl oxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound C2-3 and tetrahydropyran-4-ol.

LCMS: m/z 536 [M+H] +

HPLC retention time: 2.05 min (analysis condition S)

Compound C4-16

6,6-Dimethyl-9-(4-methyl-piperazine-1-sulfonyl)-11-oxo-8-(tetrahydro-pyran-4-yl oxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound C2-4 and tetrahydropyran-4-ol.

LCMS: m/z 549 [M+H] +

HPLC retention time: 2.03 min (analysis condition U)

Compound C4-17

8-(2-Diethylamino-ethoxy)-6,6-dimethyl-9-(4-methyl-piperazine-1-sulfonyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1, the target compound was prepared from Compound C2-3.

LCMS: m/z 564 [M+H] +

HPLC retention time: 1.20 min (analysis condition S)

Compound C5

3-Cyano-8-methoxy-5,6,6-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonic acid dimethylamide

The title compound was obtained as a by-product of the synthesis of Compound C4-3.

LCMS: m/z 438 [M+H] +

HPLC retention time: 2.29 min (analysis condition S)

Compound D0-1-1

7-Methoxy-1,1-dimethyl-6-nitro-3,4-dihydro-1H-naphthalen-2-one

Tetrabutylammonium nitrate (2.47 g, 1.07 eq.) was dissolved in dichloromethane, and added with trifluoromethanesulfonic anhydride (1.33 ml, 1.07 eq.) at 0° C. The mixture was stirred for 1 hr, added with DCM solution of 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 1.55 g, 7.59 mmol), and then stirred at 0° C. for 2 hr and 30 min. The reaction solution was added to saturated aqueous solution of sodium hydrogen carbonate and then extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (pale yellow solid, 1.144 g, 60%).

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 7. 79 (1H, s), 7. 28 (1H, s), 3. 95 (3H, s), 3. 06 (2H, t, J=6.9 Hz), 2. 64 (2H, t, J=6.9 Hz), 1.41 (6H, s).

HPLC retention time: 2.03 min (analysis condition S)

Compound D0-1-2

7-Methoxy-1,1-dimethyl-8-nitro-3,4-dihydro-1H-naphthalen-2-one

The title compound was obtained as a by-product of the synthesis of Compound D0-1-1.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 7. 44 (1H, d, J=8.6 Hz), 7. 23 (1H, d, J=8.6 Hz), 3. 84 (3H, s), 3. 07 (2H, t, J=6.9 Hz), 2. 65 (2H, t, J=6.9 Hz), 1.35 (6H, s)

HPLC retention time: 2.15 min (analysis condition S)

Compound D0-2-1

3-Bromo-8-methoxy-6,6-dimethyl-9-nitro-6,11-dihydro-5H-benzo[b]carbazole

Under the same conditions as the method for synthesizing Compound A3-1, the title compound was prepared from Compound D0-1-1.

LCMS: m/z 401, 403 [M+H] +

HPLC retention time: 3.07 min (analysis condition S)

Compound D0-2-2

3-Bromo-8-methoxy-6,6-dimethyl-7-nitro-6,11-dihydro-5H-benzo[b]carbazole

Under the same conditions as the method for synthesizing Compound A3-1, the title compound was prepared from Compound D0-1-2.

LCMS: m/z 401, 403 [M+H] +

HPLC retention time: 3.10 min (analysis condition S)

Compound D0-3-1

3-Bromo-8-methoxy-6,6-dimethyl-9-nitro-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A4, the title compound was prepared from Compound D0-2-1.

LCMS: m/z 415, 417 [M+H] +

HPLC retention time: 3.07 min (analysis condition S)

Compound D0-3-2

3-Bromo-8-methoxy-6,6-dimethyl-7-nitro-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A4, the title compound was prepared from Compound D0-2-2.

LCMS: m/z 415, 417 [M+H] +

HPLC retention time: 2.72 min (analysis condition S)

Compound D0-4-1

8-Methoxy-6,6-dimethyl-9-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A5-2, the title compound was prepared from Compound D0-3-1.

LCMS: m/z 362 [M+H] +

HPLC retention time: 2.35 min (analysis condition S)

Compound D0-4-2

8-Methoxy-6,6-dimethyl-7-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A5-2, the title compound was prepared from Compound D0-3-2.

LCMS: m/z 362 [M+H] +

HPLC retention time: 2.35 min (analysis condition S)

Compound D0-5-1

8-Hydroxy-6,6-dimethyl-9-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A6, the title compound was prepared from Compound D0-4-1.

LCMS: m/z 348 [M+H] +

HPLC retention time: 2.28 min (analysis condition S)

Compound D0-5-2

8-Hydroxy-6,6-dimethyl-7-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A6, the title compound was prepared from Compound D0-4-2.

LCMS: m/z 348 [M+H] +

HPLC retention time: 2.23 min (analysis condition S)

Compound D1

6,6-Dimethyl-8-(1-methyl-piperidin-4-yloxy)-9-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound D0-5-1 and 1-methylpiperidin-4-ol.

LCMS: m/z 445 [M+H] +

HPLC retention time: 1.64 min (analysis condition S)

Compound D2

9-Amino-6,6-dimethyl-8-(1-methyl-piperidin-4-yl oxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

6,6-Dimethyl-8-(1-methyl-piperidin-4-yloxy)-9-nitro-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound D1, 83 mg, 0.19 mmol) was dissolved in ethanol, added with aqueous solution of ammonium acetate and aqueous solution of titanium (III) chloride, and then the mixture was stirred at room temperature for 45 min. The reaction solution was added to saturated aqueous solution of sodium hydrogen carbonate and then extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues were concentrated under reduced pressure to obtain the title compound (yellow solid, 60 mg, 78%).

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 61 (1H, br. s), 8.28-8. 34 (1H, m), 7. 94-8. 00 (1H, m), 7. 57 (1H, dd, J=8.2, 1.4 Hz), 7. 46 (1H, s), 7. 19 (1H, s), 4. 93 (1. 8H, s), 4. 65 (1. 0H, s), 4.06-4. 15 (1H, m), 3. 34 (5. 7H, s), 3.16-3. 18 (2H, m), 2.55-2. 67 (2H, m), 2.17-2. 33 (5H, m), 1.89-2. 07 (2H, m), 1.65-1. 81 (8H, m)

LCMS: m/z 415 [M+H] +

HPLC retention time: 1.12 min (analysis condition S)

Compound D3-1

N-[3-Cyano-6,6-dimethyl-8-(1-methyl-piperidin-4-yl oxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl]-methanesulfonamide

Under the same conditions as the method for synthesizing Compound A9-1, the title compound was prepared from Compound D2 and methanesulfonyl chloride.

LCMS: m/z 493 [M+H] +

HPLC retention time: 1.43 min (analysis condition S)

Compound D3-2

3-Cyano-6,6-dimethyl-11-oxo-8-(1-methylpiperidin-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-9-sulfonic acid dimethylamide

Under the same conditions as the method for synthesizing Compound A9-1, the title compound was prepared from Compound D2 and dimethylsulfamoyl chloride.

1 H-NMR (270 MHz, CD 3 OD) δ: 8.34-8. 42 (2. 0H, m), 7. 85 (1. 0H, s), 7.47-7. 58 (1. 0H, m), 7. 32 (1. 0H, s), 4.73-4. 89 (1H, m), 2.75-2. 91 (8H, m), 2.38-2. 52 (2H, m), 2. 34 (3H, s), 2.06-2. 21 (2H, m), 1.87-2. 05 (2H, m), 1. 80 (6H, s).

LCMS: m/z 522 [M+H] +

HPLC retention time: 1.66 min (analysis condition S)

Compound D3-3

N-[3-Cyano-6,6-dimethyl-8-(1-methyl-piperidin-4-yl oxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl]-2-dimethylamino-acetamide

Under the same conditions as the method for synthesizing Compound A9-10, the title compound was prepared from Compound D2 and N,N-dimethylglycine.

LCMS: m/z 500 [M+H] +

HPLC retention time: 1.31 min (analysis condition S)

Compound E1

6-Bromo-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one

7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 2.0 g, 9.791 mmol) was dissolved in CH 3 CN (40 mL), added with NBS (1.92 g, 1.1 eq.), and the mixture was stirred at room temperature for 2.5 hr. The reaction solution was added to water (40 mL), and the precipitated solid was filtered to obtain the title compound (white powder, 2.55 g, 92%).

1 H-NMR (270 MHz, CDCl 3 ) δ: 7. 36 (1H, s), 6. 84 (1H, s), 3. 91 (3H, s), 3. 02 (2H, t, J=6.8 Hz), 2. 66 (2H, t, J=6.8 Hz), 1. 42 (6H, s).

LCMS: m/z 283, 285 [M+H] +

HPLC retention time: 2.67 min (analysis condition S)

Compound E2-1

9-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

6-Bromo-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound E1, 7.89 g, 27.85 mmol) and 3-hydrazino-benzonitrile (4.45 g, 1.2 eq.) were dissolved in TFA (250 mL), and stirred at 100° C. for 2 hr. TFA was removed under reduced pressure and the residues were added with saturated aqueous solution of NaHCO 3 (500 mL), followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were added with ethyl acetate. After stirring at room temperature, the precipitated solid was separated by filtration (Compound E2-2). The filtrate was concentrated under reduced pressure to obtain the title compound as a mixture with E2-2 (yellowish white powder, 2.65 g).

LCMS: m/z 381, 383 [M+H] +

HPLC retention time: 3.03 min (analysis condition S)

Compound E2-2

9-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-1-carbonitrile

The title compound was obtained as a by-product of the synthesis of Compound E2-1.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 11. 70 (1H, s), 7. 69 (1H, dd, J=8.1, 0. 8 Hz), 7. 55 (1H, s), 7. 48 (1H, dd, J=7.4, 0.8 Hz), 7. 27 (1H, s), 7. 22 (1H, dd, J=8.1, 7.4 Hz), 4. 23 (2H, s), 3. 91 (3H, s), 1. 70 (6H, s).

LCMS: m/z 381, 383 [M+H] +

HPLC retention time: 2.92 min (analysis condition S)

Compound E2-3

Compound E2-4

3,9-Dibromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole

1,9-Dibromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole

Under the same conditions as the method for synthesizing Compound A4, the title compound was prepared (as a mixture) from Compound E1.

Compound E3-1-1

9-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A4, the title compound was prepared from Compound E2-1.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 82 (1H, s), 8. 30 (2H, s+d), 8. 03 (1H, s), 7. 61 (1H, dd, J=8.2, 1.4 Hz), 7. 49 (1H, s), 4.04 (3H, s), 1. 81 (6H, s).

LCMS: m/z 395, 397 [M+H] +

HPLC retention time: 2.77 min (analysis condition S)

Compound E3-1-2

9-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-1-carbonitrile

The title compound was obtained as a by-product of the synthesis of Compound E3-1-1.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 84 (1H, s), 8. 31 (1H, s), 7. 86 (1H, dd, J=8.2, 0.9 Hz), 7. 70 (1H, d, J=7.1 Hz), 7. 47 (1H, s), 7. 43 (1H, t, J=7.8 Hz), 4. 04 (3H, s), 1. 81 (6H, s).

LCMS: m/z 395, 397 [M+H] +

HPLC retention time: 2.42 min (analysis condition S)

Compound E3-1-3

3,9-Dibromo-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A4, the title compound was prepared from Compound E2-3 and Compound E2-4 (mixture).

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 42 (1H, s), 8. 28 (1H, s), 8. 09 (1H, d, J=8.2 Hz), 7. 68 (1H, d, J=1.6 Hz), 7. 47 (1H, s), 7. 39 (1H, dd, J=8.3, 1.7 Hz), 4. 03 (3H, s), 1.78 (6H, s).

LCMS: m/z 448, 450, 452 [M+H] +

HPLC retention time: 2.93 min (analysis condition S)

Compound E3-2

9-Bromo-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

9-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E3-1-1, 1.0 g, 2.53 mmol) was dissolved in NMP (10 mL), added with NaOMe (683 mg, 5 eq.) and 1-dodecanethiol (3.0 mL, 5 eq.), and stirred at 160° C. for 1 hr. The reaction solution was added to 0.5 N aqueous solution of hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were added with MeOH, and the solid remaining after dissolution was filtered to obtain the title compound (yellow powder, 1.88 g, 65%).

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 77 (1H, s), 11. 13 (1H, d, J=2.4 Hz), 8. 31 (1H, dd, J=7.9, 2.4 Hz), 8. 25 (1H, d, J=3.0 Hz), 8. 01 (1H, s), 7. 61 (1H, d, J=7.9 Hz), 7. 28 (1H, d, J=2.4 Hz), 1.74 (6H, s).

LCMS: m/z 381, 383 [M+H] +

HPLC retention time: 2.40 min (analysis condition S)

Compound E3-3

9-Bromo-8-isopropoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound E3-2 and 2-bromopropane.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 77 (1H, s), 8. 29 (2H, s+d), 8. 01 (1H, s), 7. 60 (1H, d, J=8.1 Hz), 7. 50 (1H, s), 5. 03 (1H, m), 1. 79 (6H, s), 1. 36 (6H, d, J=5.9 Hz).

LCMS: m/z 423, 425 [M+H] +

HPLC retention time: 2.98 min (analysis condition S)

Compound E4-1

8-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3,9-dicarbonitrile

Under the same conditions as the method for synthesizing Compound A5-2, the title compound was prepared from Compound E3-1-1.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 88 (1H, br. s), 8. 43 (1H, s), 8. 30 (1H, d, J=8.2 Hz), 8. 05 (1H, d, J=0. 5 Hz), 7.65-7. 62 (2H, m), 4. 11 (3H, s), 1. 84 (6H, s).

LCMS: m/z 342 [M+H] +

HPLC retention time: 2.23 min (analysis condition S)

Compound E4-2-1

9-(3-Hydroxy-3-methyl-but-1-ynyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

9-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E3-1-1, 50 mg, 0.13 mmol), bis(acetonitrile)dichloropalladium (II) (1.64 mg, 0.05 eq.), XPhos (9.05 mg, 0.15 eq.), cesium carbonate (185 mg, 4.5 eq.) and 3-methyl-1-butyn-1-ol (18.6 μl, 1.5 eq.) were dissolved in acetonitrile and stirred at 85° C. for 2 hr. The reaction solution was added to water, and then extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by HPLC to obtain the title compound (brown solid, 21.3 mg, 42%).

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 29 (1H, d, J=8.1 Hz), 8. 11 (1H, s), 8. 00 (1H, s), 7. 57 (1H, d, J=8.1 Hz), 7. 40 (1H, s), 5. 50 (1H, s), 3. 95 (3H, s), 2. 54 (1H, s), 1. 79 (6H, s), 1. 49 (6H, s).

LCMS: m/z 399 [M+H] +

HPLC retention time: 2.10 min (analysis condition S)

Compound E4-2-2

9-Ethynyl-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

9-(3-Hydroxy-3-methyl-but-1-ynyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E4-2-1, 21.3 mg, 0.05 mmol) and sodium hydride (3.2 mg, 1.5 eq.) were dissolved in THF, and the mixture was stirred overnight at 50° C. Water was added to the reaction solution and the residues obtained after concentration under reduced pressure were purified by HPLC to obtain the title compound (brown solid, 9.6 mg, 31%).

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 26 (1H, d, J=8.2 Hz), 8. 16 (1H, s), 7. 97 (1H, s), 7. 53 (1H, d, J=8.2 Hz), 7. 41 (1H, s), 4. 32 (1H, s), 4. 00 (3H, s), 1.79 (6H, s).

LCMS: m/z 341 [M+H] +

HPLC retention time: 2.27 min (analysis condition S)

Compound E4-3

8-Methoxy-6,6-dimethyl-11-oxo-9-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

9-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E3-1-1, 50 mg, 0.13 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (1:1) (10.3 mg, 0.1 eq.), TEA (53 μl, 3 eq.) and potassium vinyltrifluoroborate (51 mg, 3 eq.) were dissolved in n-propanol and the mixture was stirred at 60° C. for 5 days. The reaction solution was added to water and then extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (brown powder, 25 mg, 19%).

LCMS: m/z 343 [M+H] +

HPLC retention time: 2.55 min (analysis condition S)

Compound E4-4

9-(2-Diethylamino-ethylsulfanyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-17, the title compound was prepared from Compound E3-1-1.

LCMS: m/z 448 [M+H] +

HPLC retention time: 2.05 min (analysis condition U)

Compound E4-5

9-Isopropylsulfanyl-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-17, the title compound was prepared from Compound E3-1-1 and sodium salt of propane-2-thiol.

LCMS: m/z 391 [M+H] +

HPLC retention time: 2.98 min (analysis condition U)

Compound E4-6

8-Methoxy-6,6-dimethyl-9-(4-methylpiperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-10, the title compound was prepared from Compound E3-1-1 and 1-methylpiperazine.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8. 25 (1H, d, J=7.8 Hz), 7. 93 (1H, s), 7. 65 (1H, s), 7. 50 (1H, d, J=6.8 Hz), 7. 25 (1H, s), 3. 93 (3H, s), 3. 02 (4H, br), 2. 22 (3H, s), 1.73 (6H, s).

LCMS: m/z 415 [M+H] +

HPLC retention time: 1.80 min (analysis condition U)

Compound E4-7-1

4-(3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

To 9-bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E3-1-1, 300 mg, 0.759 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (282 mg, 0.911 mmol, 1.2 eq.), Pd(PPh 3 ) 2 Cl 2 (26.6 mg, 0.0379 mmol, 0.05 eq.) and sodium carbonate (241 mg, 2.28 mmol, 3.0 eq.), DME (5 ml) and water (1 ml) were added. The mixture was subjected to reduced pressure under ultrasonication treatment, followed by flushing with nitrogen gas. This procedure was repeated five times and then degassed. The mixture was stirred at 80° C. for 80 min under nitrogen atmosphere. Pd(PPh 3 ) 2 Cl 2 (26.6 mg, 0.0379 mmol, 0.05 eq.) was added and the mixture was further stirred at 80° C. for 20 min. Then, the mixture was cooled to room temperature, and added with water and ethyl acetate. The insoluble matters were filtered through Celite. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure to obtain the title compound as a crude product (gray powder).

LCMS: m/z 498 [M+H] +

HPLC retention time: 2.85 min (analysis condition S)

Compound E4-7-2

8-Methoxy-6,6-dimethyl-11-oxo-9-(1,2,3,6-tetrahydro-pyridin-4-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound B4-4-1.

LCMS: m/z 368 [M+H] +

HPLC retention time: 1.27 min (analysis condition S)

Compound E4-8-1

4-(3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-piperidine-1-carboxylic acid tert-butyl ester

Under the same conditions as the method for synthesizing Compound B3-13-1, the title compound was prepared from Compound B4-7-1.

LCMS: m/z 500 [M+H] +

HPLC retention time: 4.18 min (analysis condition W)

Compound E4-8-2

8-Methoxy-6,6-dimethyl-11-oxo-9-piperidin-4-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound B4-8-1.

LCMS: m/z 400 [M+H] +

HPLC retention time: 1.35 min (analysis condition S)

Compound E4-9-1

4-(3-Cyano-8-isopropoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

Under the same conditions as the method for synthesizing Compound E4-7-1, the title compound was prepared from Compound E3-3.

LCMS: m/z 526 [M+H] +

HPLC retention time: 3.13 min (analysis condition S)

Compound E4-9-2

8-Isopropoxy-6,6-dimethyl-11-oxo-9-(1,2,3,6-tetrahydro-pyridin-4-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound E4-9-1.

LCMS: m/z 426 [M+H] +

HPLC retention time: 1.40 min (analysis condition S)

Compound E4-10

9-Cyclopropyl-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-7-1, the title compound was prepared from Compound E3-1-1 and potassium cyclopropyltrifluoroborate.

LCMS: m/z 357 [M+H] +

HPLC retention time: 2.62 min (analysis condition S)

Compound E4-11

3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-carboxylic acid

Under the same conditions as the method for synthesizing Compound B2-28, the title compound was prepared from Compound E3-1-1.

LCMS: m/z 361 [M+H] +

HPLC retention time: 1.68 min (analysis condition S)

Compound E5-1

9-Ethyl-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

The ethyl acetate suspension of 8-methoxy-6,6-dimethyl-11-oxo-9-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E4-3, 25 mg, 0.07 mmol) and palladium carbon (25 mg) were stirred at room temperature for 1 hr under hydrogen atmosphere. The reaction solution was filtered through Celite. The filtrate was concentrated under reduced pressure and the resulting residues were purified by high performance liquid chromatography to obtain the title compound (white solid, 3.2 mg, 13%).

LCMS: m/z 345 [M+H] +

HPLC retention time: 2.62 min (analysis condition S)

Compound E5-2

9-(2-Diethylamino-ethanesulfonyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-8, the title compound was prepared from Compound E4-4.

LCMS: m/z 480 [M+H] +

HPLC retention time: 1.97 min (analysis condition U)

Compound E5-3

8-Methoxy-6,6-dimethyl-11-oxo-9-(propane-2-sulfonyl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-8, the title compound was prepared from Compound E4-5.

LCMS: m/z 423 [M+H] +

HPLC retention time: 2.40 min (analysis condition U)

Compound E5-4

9-(1-Isopropyl-piperidin-4-yl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound E4-8-2 and acetone.

LCMS: m/z 442 [M+H] +

HPLC retention time: 1.48 min (analysis condition S)

Compound E5-5

8-Methoxy-6,6-dimethyl-9-(1-oxetan-3-yl-1,2,3,6-tetrahydro-pyridin-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound E4-7-2 and oxetan-3-one.

LCMS: m/z 454 [M+H] +

HPLC retention time: 1.32 min (analysis condition S)

Compound E5-6

8-Isopropoxy-6,6-dimethyl-9-(1-oxetan-3-yl-1,2,3,6-tetrahydro-pyridin-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound E4-9-2 and oxetan-3-one.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 71 (1H, s), 8. 31 (1H, d, J=8.2 Hz), 7. 99 (1H, s), 7. 94 (1H, s), 7. 58 (1H, d, J=7.6 Hz), 7. 33 (1H, s), 5. 84 (1. 0H, m), 4. 95 (1H, m), 4. 56 (4H, dt, J=17.4, 6.3 Hz), 3. 56 (1H, m), 3. 01 (2H, br), 1. 78 (6H, s), 1. 34 (6H, d, J=5.9 Hz).

LCMS: m/z 482 [M+H] +

HPLC retention time: 1.43 min (analysis condition S)

Compound E5-7

9-(4-Isopropyl-piperazin-1-carbonyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound E4-11 and 1-isopropylpiperazine.

LCMS: m/z 471 [M+H] +

HPLC retention time: 1.18 min (analysis condition S)

Compound E5-8

8-Methoxy-6,6-dimethyl-9-(morpholine-4-carbonyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound E4-11 and morpholine.

LCMS: m/z 430 [M+H] +

HPLC retention time: 1.68 min (analysis condition S)

Compound E6-1

(3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-propionic acid methyl ester

To the mixture of 9-ethynyl-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E4-2, 27 mg, 0.079 mmol), palladium (II) chloride (2.0 mg, 0.14 eq.), copper (II) chloride (25.0 mg, 2.2 eq.), and sodium acetate (14.1 mg, 2.13 eq.), methanol (1.5 mL) was added, and then the mixture was stirred at room temperature for 2 days under carbon monoxide atmosphere. The mixture was extracted with water and ethyl acetate and the insoluble matters were filtered off. The organic layer was washed with brine and dried over magnesium sulfate. The residues obtained after filtration and concentration under reduced pressure were washed with dichloromethane to obtain the title compound (13.9 mg, 44%).

LCMS: m/z 399 [M+H] +

HPLC retention time: 2.81 min (analysis condition F)

Compound E6-2

(3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-propynoic acid

(3-Cyano-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-propynoic acid methyl ester (Compound E6-1, 15.2 mg, 0.038 mmol) was dissolved in a mixture solvent of methanol (1.5 mL) and THF (0.5 mL), added with 2 N aqueous solution of potassium hydroxide (5 drops), and then stirred at room temperature overnight. 0.5 N Hydrochloric acid was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solids obtained after filtration and concentration under reduced pressure were washed with dichloromethane and purified by HPLC to obtain the title compound (white solid, 9.6 mg, 66%).

LCMS: m/z 385 [M+H] +

HPLC retention time: 2.35 min (analysis condition F)

Compound E6-3

9-(3-Hydroxy-3-methyl-butyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

9-(3-Hydroxy-3-methyl-but-1-ynyl)-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound E4-2-1, 21.0 mg, 0.0527 mmol) was dissolved in ethanol (15 mL) and N,N-dimethylacetamide (2 mL), added with 10% Pd/C (6.7 mg), and then stirred at room temperature overnight under hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure. The resulting residues were diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was washed with dichloromethane to obtain the title compound (yellow powder, 16.9 mg, 80%).

LCMS: m/z 403 [M+H] +

HPLC retention time: 5.39 min (analysis condition H)

Compound F1-1

4-(9-Bromo-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl oxy)-piperidine-1-carboxylic acid tert-butyl ester

According to the same method as the method for synthesizing Compound A7-17, the title compound was prepared from Compound E3-2 and 4-trifluoromethanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester.

LCMS: m/z 564, 566 [M+H] +

HPLC retention time: 3.30 min (analysis condition S)

Compound F1-2

9-Bromo-6,6-dimethyl-11-oxo-8-(piperidin-4-yl oxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound F1-1.

LCMS: m/z 464, 466 [M+H] +

HPLC retention time: 1.52 min (analysis condition S)

Compound F1-3

9-Bromo-8-(1-methanesulfonyl-piperidin-4-yl oxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A9-1, the title compound was prepared from Compound F1-2 and methanesulfonyl chloride.

LCMS: m/z 542, 544 [M+H] +

HPLC retention time: 2.57 min (analysis condition S)

Compound F1-4

9-Bromo-6,6-dimethyl-11-oxo-8-(tetrahydro-pyran-4-yl oxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound E3-2 and tetrahydropyran-4-ol.

LCMS: m/z 465, 467 [M+H] +

HPLC retention time: 2.70 min (analysis condition S)

Compound F2

Trifluoro-methanesulfonic acid 9-bromo-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester

Under the same conditions as the method for synthesizing Compound B1, the title compound was prepared from Compound E3-2.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 99 (1H, s), 8. 51 (1H, s), 8. 31 (1H, dd, J=8.2, 0. 7 Hz), 8. 17 (1H, s), 8. 07 (1H, s), 7. 67 (1H, dd, J=8.2, 1.4 Hz), 1. 81 (6H, s).

LCMS: m/z 513, 515 [M+H] +

HPLC retention time: 3.13 min (analysis condition S)

Compound F3-1

9-Bromo-6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-yloxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound F1-2 and oxetan-3-one.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8. 29 (1H, d, 8 Hz), 8. 29 (1H, s), 8. 01 (1H, s), 7. 60 (1H, d, 8 Hz), 7. 55 (1H, s), 5.00-4. 95 (1H, m), 4. 55 (2H, dd, 8, 8 Hz), 4. 44 (2H, dd, 8, 8 Hz), 2.52-2. 46 (1H, m), 2.33-2. 29 (2H, m), 1.96-1. 94 (2H, m), 1. 79 (8H, br. s)

LCMS: m/z 519, 521 [M+H] +

HPLC retention time: 2.78 min (analysis condition W)

Compound F3-2

9-Bromo-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound F2 and 4-pyrrolidin-1-yl-piperidine.

LCMS: m/z 517, 519 [M+H] +

HPLC retention time: 1.70 min (analysis condition S)

Compound F3-3

9-Bromo-8-(4-methanesulfonyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound F2 and 1-methanesulfonylpiperazine.

LCMS: m/z 527, 529 [M+H] +

HPLC retention time: 2.48 min (analysis condition S)

Compound F3-4

9-Bromo-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound F2 and morpholine.

LCMS: m/z 450, 452 [M+H] +

HPLC retention time: 2.65 min (analysis condition S)

Compound F3-5

9-Bromo-8-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound F2 and 2-piperazin-1-yl ethanol.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 26 (2. 0H, s+d), 7. 97 (1H, s), 7. 54 (1H, d, J=8.7 Hz), 7. 43 (1H, s), 4. 45 (1H, t, J=5.4 Hz), 3. 55 (2H, q, J=5.8 Hz), 3. 17 (4H, br), 2. 66 (2H, br), 1. 76 (6H, s).

LCMS: m/z 493, 495 [M+H] +

HPLC retention time: 1.43 min (analysis condition S)

Compound F3-6-1

[1-(9-Bromo-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound F2 and piperidin-4-yl-carbamic acid tert-butyl ester.

LCMS: m/z 563, 565 [M+H] +

HPLC retention time: 3.05 min (analysis condition S)

Compound F3-6-2

8-(4-Amino-piperidin-1-yl)-9-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound F3-6-1.

LCMS: m/z 463, 465 [M+H] +

HPLC retention time: 1.47 min (analysis condition S)

Compound F3-7

9-Bromo-8-(4-hydroxy-piperidin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound F2 and piperidin-4-ol.

LCMS: m/z 464, 466 [M+H] +

HPLC retention time: 2.25 min (analysis condition S)

Compound F3-8

9-Bromo-8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound F2 and 1-isopropylpiperazine.

LCMS: m/z 491, 493 [M+H] +

HPLC retention time: 1.58 min (analysis condition S)

Compound F3-9

9-Bromo-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound F2 and piperazine.

1 H-NMR (DMSO-d 6 ) δ: 8.30-8. 24 (2H, m), 8. 00 (1H, s), 7.63-7. 58 (1H, m), 7. 37 (1H, s), 3. 10-3. 01 (4H, m), 2.91-2. 85 (4H, m), 1. 76 (6H, s)

LCMS: m/z 449, 451 [M+H] +

HPLC retention time: 1.45 min (analysis condition S)

Compound F3-10

4-(9-Bromo-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperazine-1-carboxylic acid tert-butyl ester

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound F2 and piperazine-1-carboxylic acid tert-butyl ester.

LCMS: m/z 549, 551 [M+H] +

HPLC retention time: 4.61 min (analysis condition W)

Compound F3-11

9-Bromo-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound F2 and 4-piperidin-4-yl morpholine.

1 H-NMR (DMSO-d 6 ) δ: 8.30-8. 24 (2H, m), 8. 00 (1H, s), 7. 59 (1H, d, J=8. 2 Hz), 7. 42 (1H, s), 3.66-3. 45 (6H, m), 2. 80 (2H, t, J=11.1 Hz), 2.38-2. 28 (1H, m), 1.96-1. 87 (2H, m), 1. 75 (6H, s), 1.66-1. 56 (2H, m)

LCMS: m/z 533, 535 [M+H] +

HPLC retention time: 1.53 min (analysis condition S)

Compound F4-1-1

9-Ethynyl-6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-yloxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-43, the title compound was prepared from Compound F3-1.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8. 30 (1H, d, 8 Hz), 8. 17 (1H, s), 8. 01 (1H, s), 7. 60 (1H, d, 8 Hz), 7. 50 (1H, s), 4.87-4. 83 (1H, m), 4. 55 (2H, dd, 4, 4 Hz), 4. 45 (2H, dd, 4, 4 Hz), 3. 44 (1H, ddd, 4, 4, 4 Hz), 2.33-2. 24 (2H, m), 1.99-1. 91 (2H, m), 1. 78 (8H, br. s)

LCMS: m/z 466 [M+H] +

HPLC retention time: 2.67 min (analysis condition W)

Compound F4-1-2

9-Ethyl-6,6-dimethyl-8-(1-oxetan-3-yl-piperidin-4-yloxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-13-1, the title compound was prepared from Compound F4-1-1.

LCMS: m/z 470 [M+H] +

HPLC retention time: 2.74 min (analysis condition W)

Compound F4-2

N-[1-(9-Bromo-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidin-4-yl]-methanesulfonamide

Under the same conditions as the method for synthesizing Compound A9-1, the title compound was prepared from Compound F3-6-2 and methanesulfonyl chloride.

LCMS: m/z 541, 543 [M+H] +

HPLC retention time: 2.37 min (analysis condition S)

Compound F4-3

9-Bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound F3-9 and 1-oxetan-3-one.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 83 (1H, br. s), 8.31-8. 32 (1H, m), 8. 27-8. 29 (1H, m), 8.01-8. 04 (1H, m), 7.59-7. 64 (1H, m), 7. 48 (1H, s), 4. 59 (2H, dd, J=6. 3, 6.3 Hz), 4. 48 (2H, dd, J=6. 3, 6. 3 Hz), 3. 52 (1H, t, J=6. 3 Hz), 3.12-3. 25 (4H, m), 2.44-2. 54 (4H, m), 1. 78 (6H, s).

LCMS: m/z 505, 507 [M+H] +

HPLC retention time: 1.45 min (analysis condition S)

Hydrochloric Acid Salt of Compound F4-3

9-Bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile was added with DMSO and 6 N hydrochloric acid (1.05 eq.) and dissolved therein. After freeze-drying, crystallization was performed by using ethanol comprising 25% water to obtain monohydrochloric acid salt of 9-bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 91 (1H, br. s), 11. 70 (1H, br. s), 8.32-8. 29 (2H, m), 8. 04 (1H, s), 7.64-7. 62 (1H, m), 7. 52 (1H, s), 4.89-4. 62 (4H, br. m), 3.66-3. 39 (1H, m), 3.31-3. 05 (8H, br. m), 1. 81 (6H, s)

LCMS: m/z 505, 507 [M+H] +

Compound F4-4

9-Bromo-8-{4-[2-(2-methoxy-ethoxy)-ethyl]-piperazin-1-yl}-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound F3-9 and 1-bromo-2-(2-methoxyethoxy)ethane.

LCMS: m/z 551, 553 [M+H] +

HPLC retention time: 2.80 min (analysis condition W)

Compound F4-5

9-Bromo-6,6-dimethyl-11-oxo-8-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound F3-9 and tetrahydropyran-4-one.

LCMS: m/z 533, 535 [M+H] +

HPLC retention time: 2.67 min (analysis condition W)

Compound F4-6

9-Bromo-6,6-dimethyl-11-oxo-8-[4-(tetrahydro-thiopyran-4-yl)-piperazin-1-yl]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound F3-9 and tetrahydrothiopyran-4-one.

LCMS: m/z 549, 551 [M+H] +

HPLC retention time: 2.86 min (analysis condition W)

Compound F4-7

9-Bromo-8-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-piperazin-1-yl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-8, the title compound was prepared from Compound F4-6.

LCMS: m/z 581, 583 [M+H] +

HPLC retention time: 2.66 min (analysis condition W)

Compound F4-8

9-Bromo-8-(4-cyclopropylmethyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound F3-9 and bromomethylcyclopropane.

LCMS: m/z 503, 505 [M+H] +

HPLC retention time: 2.81 min (analysis condition W)

Compound F4-9

9-Bromo-8-(4-cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound F3-9 and (1-ethoxy-cyclopropoxy)-trimethyl-silane.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8.22-8. 30 (2H, m), 8. 00 (1H, s), 7. 56 (1H, d, J=7.9 Hz), 7. 43 (1H, s), 3. 30 (1H, d, J=5.8 Hz), 3. 11 (4H, s), 2. 75 (4H, s), 1. 75 (6H, s), 0.47 (2H, d, J=5.8 Hz), 0.34 (2H, d, J=5.8 Hz)

LCMS: m/z 489, 491 [M+H] +

HPLC retention time: 1.68 min (analysis condition S)

Compound F4-10

9-Bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound F3-9 and cyclobutanone.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8.23-8. 29 (2H, m), 8. 00 (1H, s), 7. 55 (1H, d, 7.9 Hz), 7. 45 (1H, s), 4.04-4. 15 (1H, m), 3. 10-3. 20 (4H, m), 2.39-2. 48 (4H, m), 1. 97-2. 06 (2H, m), 1.78-1. 88 (2H, m), 1. 77 (6H, s), 1.61-1. 72 (2H, m)

LCMS: m/z 503, 505 [M+H] +

HPLC retention time: 2.78 min (analysis condition W)

Compound F5-1

9-Ethynyl-8-(4-methanesulfonyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-43, the title compound was prepared from Compound F3-3.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 78 (1H, s), 8. 31 (1H, dd, J=8.1, 0. 7 Hz), 8. 19 (1H, s), 8. 02 (1H, dd, J=1. 4, 0. 7 Hz), 7. 61 (1H, dd, J=8.2, 1. 4 Hz), 7. 33 (1H, s), 4. 55 (1H, s), 3. 43 (4H, br), 2. 98 (3H, s), 1. 79 (6H, s).

LCMS: m/z 473 [M+H] +

HPLC retention time: 2.27 min (analysis condition S)

Compound F5-2

N-[1-(3-Cyano-9-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidin-4-yl]-methanesulfonamide

Under the same conditions as the method for synthesizing Compound F5-43, the title compound was prepared from Compound F4-2.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 98 (1H, s), 8. 30 (1H, d, J=8.1 Hz), 8. 15 (1H, s), 8. 02 (1H, s), 7. 61 (1H, d, J=7.9 Hz), 7. 23 (2H, s+d), 4. 55 (1H, s), 3. 79 (2H, brd), 2. 95 (4H, br), 1. 96 (2H, brd), 1.78 (3H, s), 1. 65 (2H, brd).

LCMS: m/z 487 [M+H] +

HPLC retention time: 2.15 min (analysis condition S)

Compound F5-3

6,6-Dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3,9-dicarbonitrile

Under the same conditions as the method for synthesizing Compound A5-2, the target compound was prepared from Compound F3-2.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 33 (1H, d, J=1.3 Hz), 8. 27 (1H, dd, J=7.7, 1.3 Hz), 8. 00 (1H, s), 7. 57 (1H, d, J=7.7 Hz), 7. 40 (1H, s), 3. 74 (2H, m), 3. 19-3.33 (1H, m), 2.98-3. 12 (2H, m), 2.35-2. 62 (2H, m), 2.11-2. 29 (2H, m), 1.89-2. 06 (2H, m), 1. 78 (6H, s), 1.54-1. 70 (6H, m).

LCMS: m/z 464 [M+H] +

HPLC retention time: 1.55 min (analysis condition S)

Compound F5-4

9-Ethynyl-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1 and Compound E4-2-2, the title compound was prepared from Compound F3-2.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 29 (1H, d, J=8.2 Hz), 8. 14 (1H, s), 8. 00 (1H, s), 7. 58 (1H, dd, J=8.1, 1.3 Hz), 7. 24 (1H, s), 4. 50 (1H, s), 3.70-3. 83 (2H, m), 3.34-3. 48 (1H, m), 2.83-2. 98 (2H, m), 2.45-2. 58 (2H, m), 2. 10-2. 23 (2H, m), 1. 90-2. 03 (2H, m), 1. 76 (6H, s), 1.51-1. 74 (6H, m).

LCMS: m/z 463 [M+H] +

HPLC retention time: 1.60 min (analysis condition S)

Compound F5-5

9-Ethynyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1 and Compound E4-2-2, the title compound was prepared from Compound F3-4.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 82 (1H, s), 8. 31 (1H, d, J=7.9 Hz), 8. 18 (1H, s), 8. 02 (1H, s), 7. 61 (1H, d, J=7.9 Hz), 7. 28 (1H, s), 4. 53 (1H, s), 3. 80 (4 H, s), 3. 36 (4H, s), 1. 79 (6H, s).

LCMS: m/z 396 [M+H] +

HPLC retention time: 2.32 min (analysis condition S)

Compound F5-6

9-(3-Dimethylamino-prop-1-ynyl)-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the title compound was prepared from Compound F3-4 and 3-dimethylaminopropyne.

1 H-NMR (270 MHz, CDCl 3 ) δ: 8. 52 (1H, d, J=7.8 Hz), 8. 47 (1H, s), 7. 76 (1H, s), 7. 56 (1H, d, J=7.8 Hz), 7. 03 (1H, s), 3. 92 (4H, m), 3. 55 (2H, s), 3. 39 (4H, m), 2. 37 (6H, s), 1. 83 (6H, s)

LCMS: m/z 453 [M+H] +

Compound F5-7

6,6-Dimethyl-8-morpholin-4-yl-9-(3-morpholin-4-yl-prop-1-ynyl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To 9-bromo-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound F3-4, 30 mg, 0.067 mmol), 3-bromopropyne (0.01 ml, 0.13 mmol), morpholine (0.029 ml, 0.33 mmol), X-Phos (4.8 mg, 15% mol), PdCl 2 (CH 3 CN) 2 (0.9 mg, 5% mol) and cesium carbonate (87 mg, 0.27 mmol), acetonitrile (2 ml) was added and the mixture was stirred at 80° C. for 2 hr. The reaction solution was added to water, and then extracted with dichloromethane. The organic layer was dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (dichloromethane/methanol) to obtain the target compound (pale brown solid, 18 mg, 64%).

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 29 (1H, d, J=7.8 Hz), 8. 14 (1H, s), 8. 00 (1H, s), 7. 59 (1H, d, J=7.8 Hz), 7. 27 (1H, s), 3. 79 (4H, m), 3. 64 (4H, m), 3. 61 (2H, s), 3. 33 (4H, m), 2. 56 (4H, m), 1. 77 (6H, s)

LCMS: m/z 495 [M+H] +

Compound F5-8

6,6-Dimethyl-8-morpholin-4-yl-11-oxo-9-pent-1-ynyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the title compound was prepared from Compound F3-4 and 1-pentyne.

LCMS: m/z 438 [M+H] +

HPLC retention time: 2.88 min (analysis condition S)

Compound F5-9

9-(3-Methoxy-prop-1-ynyl)-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the title compound was prepared from Compound F3-4 and 3-methoxypropyne.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 30 (1H, d, J=7.8 Hz), 8. 15 (1H, s), 8. 01 (1H, s), 7. 60 (1H, d, J=7.8 Hz), 7. 28 (1H, s), 4. 41 (2H, s), 3. 79 (4H, m), 3. 37 (3H, s), 3. 34 (4H, m), 1. 78 (6H, s)

LCMS: m/z 440 [M+H] +

Compound F5-10

9-[3-(4-Cyclopropyl-piperazin-1-yl)-prop-1-ynyl]-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-7, the title compound was prepared from Compound F3-4 and 3-bromopropyne and 4-cyclopropylpiperazine.

LCMS: m/z 534 [M+H] +

HPLC retention time: 1.40 min (analysis condition S)

Compound F5-11

6,6-Dimethyl-9-(1-methyl-1H-pyrazol-4-yl)-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-7-1, the title compound was prepared from Compound F3-4 and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8. 29 (1H, d, J=7.8 Hz), 8. 22 (1H, s), 8. 09 (1H, s), 7.99 (1H, s), 7. 95 (1H, s), 7.56-7. 61 (1H, m), 7. 36 (1H, s), 3. 90 (3H, s), 3. 73 (4H, s), 2. 95 (4H, s), 1. 77 (6H, s).

LCMS: m/z 452 [M+H] +

HPLC retention time: 2.18 min (analysis condition U)

Compound F5-12

9-Cyclopropyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-7-1, the title compound was prepared from Compound F3-4 and potassium cyclopropyltrifluoroborate.

1 H-NMR (270 MHz, CD 3 OD+CDCl 3 ) δ: 8. 45 (1H, d, J=7.8 Hz), 7. 83 (2H, m), 7. 54 (1H, d, J=7.8 Hz), 7. 20 (1H, s), 3. 96 (4H, m), 3.24 (4H, m), 2. 25 (1H, m), 1. 80 (6H, s), 1.09 (2H, m), 0. 93 (2H, m)

LCMS: m/z 412 [M+H] +

Compound F5-13

6,6-Dimethyl-8-morpholin-4-yl-11-oxo-9-vinyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-24, the title compound was prepared from Compound F3-4 and potassium vinyltrifluoroborate.

LCMS: m/z 398 [M+H] +

HPLC retention time: 2.67 min (analysis condition U)

Compound F5-14

9-Ethynyl-8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-43, the title compound was prepared from Compound F3-8.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 73 (1H, s), 8. 31 (1H, d, J=9.1 Hz), 8. 16 (1H, d, J=1. 2 Hz), 8. 00 (1H, s), 7. 60 (1H, d, J=7. 9 Hz), 7. 25 (1H, s), 4. 50 (1H, d, J=1.8 Hz), 2. 72 (1H, m), 2. 65 (4H, s), 1. 78 (6H, s), 1. 04 (6H, d, J=5.5 Hz).

LCMS: m/z 437 [M+H] +

HPLC retention time: 1.48 min (analysis condition S)

Compound F5-15-1

4-(3-Cyano-9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperazine-1-carboxylic acid tert-butyl ester

Under the same conditions as the method for synthesizing Compound E4-7-1, the title compound was prepared from Compound F3-10 and potassium cyclopropyltrifluoroborate.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8. 55 (1H, s), 8.28-8. 25 (1H, m), 7.98-7. 95 (1H, m), 7. 62 (1H, s), 7. 32 (1H, s), 3.56-3. 53 (4 h, m), 3.09-3. 07 (4H, m), 2.22-2. 18 (1H, m), 1. 73 (6H, br s), 1. 44 (9H, s), 1.08-1. 05 (2H, m), 0.77-0.76 (2H, m)

LCMS: m/z 511 [M+H] +

HPLC retention time: 4.50 min (analysis condition W)

Compound F5-15-2

9-Cyclopropyl-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound F5-15-1.

LCMS: m/z 411 [M+H] +

HPLC retention time: 2.67 min (analysis condition W)

Compound F5-16

9-Ethynyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-43, the title compound was prepared from Compound F4-3.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 77 (1H, br. s), 8. 31 (1H, d, J=8.2 Hz), 8. 16 (1H, s), 8. 02 (1H, s), 7. 61 (1H, dd, J=8.2, 1.3 Hz), 7. 27 (1H, s), 4. 59 (2H, dd, J=6.6, 6.6 Hz), 4. 51 (1H, s), 4. 49 (2H, dd, J=6.6, 6.6 Hz), 3. 51 (1H, t, J=6.6 Hz), 3.35-3. 43 (4H, m), 2.43-2. 50 (4H, s), 1. 78 (6H, s).

LCMS: m/z 451 [M+H] +

HPLC retention time: 1.40 min (analysis condition S)

Compound F5-17

6,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3,9-dicarbonitrile

According to the same method as the method for synthesizing Compound A5-2, the title compound was prepared from Compound F4-3.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 84 (1H, br. s), 8. 36 (1H, s), 8.32-8. 29 (1H, d, 8.08 Hz), 8. 04 (1H, s), 7.65-7. 62 (1H, d, 8.08 Hz), 7. 44 (1H, s), 4.62-4. 57 (2H, m), 4.52-4. 47 (2H, m), 3.81-3. 78 (2H, t, 4.61 Hz), 3.57-3. 50 (1H, m), 3. 43 (4H, m) 2. 51 (4H, m), 1. 80 (6H, s)

LCMS: m/z 452 [M+H] +

Compound F5-18

9-(3-Methoxy-prop-1-ynyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the title compound was prepared from Compound F4-3 and 3-methoxypropyne.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 77 (1H, br. s), 8.32-8. 29 (1H, d, 8. 08 Hz), 8. 13 (1H, s), 8. 01 (1H, s), 7.62-7. 59 (1H, d, 8.08 Hz), 7. 27 (1H, s), 4.62-4. 57 (2H, m), 4.52-4. 47 (2H, m), 4. 39 (2H, s), 3.53-3. 47 (1H, m), 3. 38 (4H, m), 3. 36 (3H, s), 2. 51 (4H, m), 1. 77 (6H, s)

LCMS: m/z 495 [M+H] +

Compound F5-19

9-(3-Dimethylamino-prop-1-ynyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the title compound was prepared from Compound F4-3 and dimethyl-prop-2-ynylamine.

LCMS: m/z 508 [M+H] +

HPLC retention time: 1.07 min (analysis condition S)

Compound F5-20

6,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-9-[3-(4-oxetan-3-yl-piperazin-1-yl)-prop-1-ynyl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-7, the title compound was prepared from Compound F4-3, 3-bromopropyne and 4-oxetan-3-yl-piperazine.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 30 (1H, d, J=7.8 Hz), 8. 12 (1H, s), 8. 00 (1H, s), 7. 59 (1H, d, J=7.8 Hz), 7. 26 (1H, s), 4.60-4. 42 (8H, m), 3. 61 (2H, s), 3. 60-3. 30 (6H, m), 2.60-2. 30 (12H, m), 1. 77 (6H, s)

LCMS: m/z 605 [M+H] +

Compound F5-21

9-Cyclopentylethynyl-6,6-dimethyl-8-(4-oxetan-3-yl piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the title compound was prepared from Compound F4-3 and cyclopentylacetylene.

LCMS: m/z 519 [M+H] +

HPLC retention time: 1.80 min (analysis condition S)

Compound F5-22

6,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the title compound was prepared from Compound F4-3 and propyne.

1 H-NMR (400 MHz, CD 3 OD) δ: 8. 37 (1H, d, J=8.2 Hz), 8. 18 (1H, s), 7. 84 (1H, s), 7. 53 (1H, d, J=8.2 Hz), 7. 19 (1H, s), 4.70-4. 77 (2H, m), 4.62-4. 68 (2H, m), 3.57-3. 63 (1H, m), 3.38-3. 45 (4H, m), 2.54-2. 61 (4H, m), 2. 10 (3H, s), 1. 79 (6H, s)

LCMS: m/z 465 [M+H] +

HPLC retention time: 1.90 min (analysis condition U)

Compound F5-23

9-(3-Hydroxy-prop-1-ynyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the TMS complex of the title compound was prepared from Compound F4-3 and trimethylprop-2-ynyloxysilane. By treating the resulting TMS complex with tetrabutylammonium fluoride, the title compound was obtained.

LCMS: m/z 481 [M+H] +

HPLC retention time: 1.30 min (analysis condition S)

Compound F5-24

6,6-Dimethyl-9-(4-methyl-pent-1-ynyl)-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the title compound was prepared from Compound F4-3 and 4-methylpent-1-yne.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 75 (1H, br. s), 8.32-8. 29 (1H, d, 8. 08 Hz), 8. 08 (1H, s), 8. 01 (1H, s), 7.62-7. 59 (1H, m), 7. 23 (1H, s), 4.61-4. 57 (2H, m), 4.51-4. 46 (2H, m), 3.51-3. 47 (1H, m), 3. 37 (4H, m), 2. 46 (4H, m), 2.41-2. 39 (2H, d, 5.94 Hz), 1.92-1. 80 (1H, m), 1.77 (6H, s), 1.04 (3H, s), 1.01 (3H, s)

LCMS: m/z 507 [M+H] +

Compound F5-25

9-Cyclopropylethynyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the title compound was prepared from Compound F4-3 and ethynylcyclopropane.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 74 (1H, br. s), 8.32-8. 29 (1H, d, 8. 08 Hz), 8. 05 (1H, s), 8. 00 (1H, s), 7.62-7. 58 (1H, m), 7. 21 (1H, s), 4.62-4. 57 (2H, m), 4.51-4. 47 (2H, m), 3.53-3. 48 (1H, m), 3. 34 (4H, m), 2. 46 (4H, m), 1.76 (6H, s), 1. 64-1. 58 (1H, m), 0.97-0.89 (2H, m), 0.76-0.70 (2H, m)

LCMS: m/z 491 [M+H] +

Compound F5-26

6,6-Dimethyl-9-(3-morpholin-4-yl-prop-1-ynyl)-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-7, the title compound was prepared from Compound F4-3, 3-bromopropyne and morpholine.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 29 (1H, d, J=7.8 Hz), 8. 13 (1H, s), 8. 02 (1H, s), 7. 59 (1H, d, J=7.8 Hz), 7. 25 (1H, s), 4.61-4. 48 (4H, m), 3.64-3. 32 (11H, m), 2.60-2.40 (8H, m), 1. 78 (6H, s)

LCMS: m/z 550 [M+H] +

Compound F5-27

6,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-pent-1-ynyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the title compound was prepared from Compound F4-3 and 1-pentyne.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 72 (1H, br. s), 8. 28 (1H, d, 8.1 Hz), 8. 06 (1H, s), 7. 98 (1H, s), 7. 58 (1H, d, 8.1 Hz), 7.21 (1H, s), 4.60-4. 43 (4H, m), 3. 53-3. 44 (1H, m), 3.39-3. 32 (2H, m), 1. 75 (6H, s), 1. 60-1. 53 (4H, m), 1.01 (3H, t, 7. 3 Hz)

LCMS: m/z 493 [M+H] +

HPLC retention time: 2.17 min (analysis condition U)

Compound F5-28

6,6-Dimethyl-9-(5-methyl-hex-1-ynyl)-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the title compound was prepared from Compound F4-3 and 5-methylhex-1-yne.

LCMS: m/z 521 [M+H] +

HPLC retention time: 2.37 min (analysis condition U)

Compound F5-29

9-(3-Diethylamino-prop-1-ynyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the title compound was prepared from Compound F4-3 and 3-diethylaminopropyne.

LCMS: m/z 536 [M+H] +

HPLC retention time: 1.13 min (analysis condition S)

Compound F5-30

9-[3-(Benzyl-ethyl-amino)-prop-1-ynyl]-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the title compound was prepared from Compound F4-3 and 3-benzyl-3-ethylaminopropyne.

LCMS: m/z 584 [M+H] +

HPLC retention time: 1.32 min (analysis condition S)

Compound F5-31

9-[3-(1,1-Dioxo-1λ6-thiomorpholin-4-yl)-prop-1-ynyl]-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the title compound was prepared from Compound F4-3 and 3-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-propyne.

LCMS: m/z 598 [M+H] +

HPLC retention time: 1.35 min (analysis condition S)

Compound F5-32

9-Isopropenyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-7-1, the title compound was prepared from Compound F4-3 and 2-isopropenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane.

1 H-NMR (270 MHz, CD 3 OD+CDCl 3 ) δ: 8. 44 (1H, d, J=7.8 Hz), 8. 09 (1H, s), 7. 83 (1H, s), 7. 54 (1H, d, J=7.8 Hz), 7. 18 (1H, s), 5.24-5. 20 (2H, m), 4.81-4. 68 (4H, m), 3. 66 (1H, m), 3. 30 (4H, m), 2. 57 (4H, m), 2.21 (3H, s), 1. 82 (6H, s)

LCMS: m/z 467 [M+H] +

Compound F5-33

6,6,9-Trimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-47, the title compound was prepared from Compound F4-3.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 71 (1H, br. s), 8.33-8. 31 (1H, d, 8. 08 Hz), 8. 01 (1H, s), 7. 97 (1H, s), 7.62-7. 59 (1H, m), 7. 32 (1H, s), 4.61-4. 57 (2H, m), 4.51-4. 47 (2H, m), 3.55-3. 49 (1H, m), 3. 05 (4H, m), 2. 47 (4H, m), 2. 33 (3H, s), 1. 76 (6H, s)

LCMS: m/z 441 [M+H] +

Compound F5-34

9-Cyclopropyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound F5-15-2 and oxetan-3-one.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8.32-8. 29 (1H, m), 8.00-7. 99 (1H, m), 7. 62-7. 58 (2H, m), 7.32-7. 31 (1H, m), 4.61-4. 57 (2H, m), 4.52-4. 49 (2H, m), 3. 53 (1H, br. s), 3. 18 (4H, br. s), 1. 75 (6H, s), 1.25-1. 23 (1H, m), 1.09-1. 04 (2H, m), 0.79-0.75 (2H, m)

LCMS: m/z 467 [M+H] +

HPLC retention time: 2.74 min (analysis condition W)

Compound F5-35

6,6-Dimethyl-9-(1-methyl-1H-pyrazol-4-yl)-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-7-1, the title compound was prepared from Compound F4-3 and 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole.

LCMS: m/z 507 [M+H] +

HPLC retention time: 1.75 min (analysis condition U)

Compound F5-36-1

4-[3-Cyano-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazol-9-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

Under the same conditions as the method for synthesizing Compound E4-7-1, the title compound was prepared from Compound F3-2.

LCMS: m/z 621 [M+H] +

HPLC retention time: 2.58 min (analysis condition U)

Compound F5-36-2

6,6-Dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-9-(1,2,3,6-tetrahydro-pyridin-4-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound F5-36-1.

LCMS: m/z 520 [M+H] +

HPLC retention time: 1.82 min (analysis condition U)

Compound F5-37

8-(4-Cyclopropyl-piperazin-1-yl)-9-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-43, the title compound was prepared from Compound F4-9.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 76 (1H, br. s), 8. 31 (1H, d, J=8.1 Hz), 8. 15 (1H, s), 8. 01 (1H, s), 7. 61 (1H, dd, J=8.1, 1.5 Hz), 7. 24 (1H, s), 4. 52 (1H, s), 3.28-3. 36 (4H, m), 3. 17 (1H, d, J=5.3 Hz), 2.70-2. 77 (4H, m), 1.76 (6H, s), 0. 47 (2H, d, J=5. 3 Hz), 0. 36 (2H, d, J=5. 3 Hz).

LCMS: m/z 435 [M+H] +

HPLC retention time: 1.57 min (analysis condition S)

Compound F5-38

8-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the title compound was prepared from Compound F4-9 and propyne.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 76 (1H, br. s), 8.31-8. 28 (1H, d, 8. 08 Hz), 8. 06 (1H, s), 8. 00 (1H, s), 7.60-7. 57 (1H, m), 7. 19 (1H, s), 3. 29 (4H, m), 2. 74 (4H, m), 2. 55 (1H, m), 2. 13 (3H, s), 1. 75 (6H, s), 0.51-0.43 (2H, m), 0.38-0.32 (2H, m)

LCMS: m/z 449 [M+H] +

Compound F5-39

8-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-phenyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-7-1, the title compound was prepared from Compound F4-9 and phenylboric acid.

LCMS: m/z 487 [M+H] +

HPLC retention time: 2.15 min (analysis condition U)

Compound F5-40

8-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-pyridin-3-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-7-1, the title compound was prepared from Compound F4-9 and pyridine-3-boric acid.

LCMS: m/z 488 [M+H] +

HPLC retention time: 1.53 min (analysis condition U)

Compound F5-41

8-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-thiophene-2-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-7-1, the title compound was prepared from Compound F4-9 and thiophene-2-boric acid.

LCMS: m/z 493 [M+H] +

HPLC retention time: 2.13 min (analysis condition U)

Compound F5-42

8-(4-Cyclopropyl-piperazin-1-yl)-6,6,9-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-47, the title compound was prepared from Compound F4-9.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 71 (1H, br. s), 8.33-8. 30 (1H, d, 8. 08 Hz), 8. 00 (1H, s), 7. 96 (1H, s), 7.61-7. 58 (1H, m), 7. 29 (1H, s), 2. 97 (4H, m), 2. 73 (4H, m), 2. 56 (1H, m), 2. 34 (3H, s), 1.76 (6H, s), 1. 64-1. 58 (1H, m), 0.50-0.44 (2H, m), 0.37-0.32 (2H, m)

LCMS: m/z 425 [M+H] +

Compound F5-43

8-(4-Cyclobutyl-piperazin-1-yl)-9-ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under nitrogen atmosphere, to the MeCN (8 ml) suspension of 9-bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound F4-10, 200 mg, 0.397 mmol), ethynyltriisopropylsilane (268 mg, 3.0 eq.), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos) (39 mg, 0.2 eq.), Pd(CH 3 CN) 2 Cl 2 (11 mg, 0.1 eq.) and cesium carbonate (518 mg, 4.0 eq.) were added and the mixture was stirred and heated under reflux condition until the reaction is completed. Upon the completion of the reaction, distilled water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/methanol) to obtain 8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-[(triisopropylsilanyl)-ethynyl]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (179 mg, 74%).

To the THF (6 ml) solution of the obtained compound (179 mg, 0.295 mmol), 1 M THF solution (710 μl) of tetrabutylammonium fluoride was added and the mixture was stirred until the reaction is completed. Upon the completion of the reaction, ethyl acetate was added to the reaction solution, which was then washed with distilled water and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were washed with a mixture solvent of ethanol and distilled water to obtain the title compound (67 mg, 92%).

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 85 (1H, s), 8. 31 (1H, d, 7.9 Hz), 8. 20 (1H, s), 8. 03 (1H, s), 7. 62 (1H, d, 7.9 Hz), 7. 35 (1H, s), 4. 62 (1H, s), 3.94-4. 03 (2H, m), 3.79-3. 89 (1H, m), 3.48-3. 54 (2H, m), 3.27-3. 38 (2H, m), 2.96-3. 16 (2H, m), 2. 30-2. 41 (2H, m), 2.16-2. 26 (2H, m), 1.72-1. 85 (8H, m)

LCMS: m/z 449 [M+H] +

HPLC retention time: 2.69 min (analysis condition W)

Compound F5-44

8-(4-Cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the title compound was prepared from Compound F4-10 under propyne gas atmosphere.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 71 (1H, s), 8. 30 (1H, d, 7.9 Hz), 8. 06 (1H, s), 8. 00 (1H, s), 7. 59 (1H, d, 7.9 Hz), 7.20 (1H, s), 2.75-2. 83 (1H, m), 2.40-2.48 (4H, m), 2. 11 (3H, s), 1.97-2. 06 (2H, m), 1. 76 (6H, s), 1.62-1. 71 (2H, m)

LCMS: m/z 463 [M+H] +

HPLC retention time: 2.80 min (analysis condition W)

Compound F5-45

9-Cyclobutylethynyl-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the title compound was prepared from Compound F4-10 and ethynylcyclobutane.

LCMS: m/z 503 [M+H] +

HPLC retention time: 1.85 min (analysis condition S)

Compound F5-46

8-(4-Cyclobutyl-piperazin-1-yl)-9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound F5-15-2 and cyclobutanone.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 8. 23 (1H, d, 8 Hz), 7. 92 (1H, br. s), 7. 59 (1H, s), 7. 47 (1H, br. d, 8 Hz), 7. 28 (1H, s), 3. 12 (4H, br. s), 2. 80 (1H, dddd, 8, 8, 8, 8 Hz), 2. 20-2. 13 (1H, m), 2. 01 (2H, br. s), 1.86-1. 68 (10H, m), 1. 05 (2H, d, 8 Hz), 0.76 (2H, d, 4 Hz)

LCMS: m/z 465 [M+H] +

HPLC retention time: 2.79 min (analysis condition W)

Hydrochloric Acid Salt of Compound F5-46

8-(4-Cyclobutyl-piperazin-1-yl)-9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile was added with DMSO and 6 N hydrochloric acid (1.05 eq.) and dissolved therein. After freeze-drying, crystallization was performed by using ethanol comprising 25% water to obtain monohydrochloric acid salt of 8-(4-cyclobutyl-piperazin-1-yl)-9-cyclopropyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 81 (1H, s), 10. 64 (1H, br. s), 8.32-8. 29 (1H, m), 8. 01 (1H, s), 7. 67 (1H, s), 7.61-7. 60 (1H, m), 7. 33 (1H, s), 4.00-3. 39 (6H, m), 3. 28-3. 02 (3H, m), 2.45-2. 05 (5H, m), 1.83-1. 77 (8H, m), 1.09-1. 07 (2H, m), 0.81-0. 80 (2H, m)

LCMS: m/z 465 [M+H] +

Compound F5-47

8-(4-Cyclobutyl-piperazin-1-yl)-6,6,9-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under nitrogen atmosphere, to the N,N-dimethyl formamide (1.5 ml) solution of 9-bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound F4-10, 50 mg, 0.099 mmol), trimethyl boroxine (12 mg, 0.1 eq.), tetrakis triphenylphosphine palladium (39 mg, 0.2 eq.), and potassium carbonate (41 mg, 3.0 eq.) were added, and the mixture was stirred at 100° C. for 24 hr. Upon the completion of the reaction, distilled water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/methanol) to obtain the title compound (25 mg, 58%).

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 67 (1H, s), 8. 31 (1H, d, 7.9 Hz), 7. 98 (1H, s), 7. 95 (1H, s), 7. 59 (1H, d, 7.9 Hz), 7. 30 (1H, s), 2.96-3. 04 (4H, m), 2.76-2. 84 (1H, m), 2.39-2. 48 (4H, m), 2. 32 (3H, s), 1.78-1. 87 (2H, m), 1. 75 (6H, s), 1.63-1. 71 (2H, m)

LCMS: m/z 439 [M+H] +

HPLC retention time: 2.66 min (analysis condition W)

Compound F5-48

8-(4-Cyclobutyl-piperazin-1-yl)-9-isopropenyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-7-1, the title compound was prepared from Compound F4-10 and 2-isopropenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane.

LCMS: m/z 465 [M+H] +

HPLC retention time: 1.63 min (analysis condition S)

Compound F5-49

9-Ethynyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-43, the title compound was prepared from Compound F3-11.

LCMS: m/z 479 [M+H] +

HPLC retention time: 1.90 min (analysis condition U)

Compound F5-50

6,6-Dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-9-prop-1-ynyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the title compound was prepared from Compound F3-11 and propyne gas.

1 H-NMR (270 MHz, CD 3 OD+CDCl 3 ) δ: 8. 40 (1H, d, J=7.8 Hz), 8. 24 (1H, s), 7. 84 (1H, s), 7. 54 (1H, d, J=7. 8 Hz), 7. 14 (1H, s), 4.01-3. 96 (2H, m), 3. 78 (4H, m), 2.88-2. 84 (2H, m), 2. 68 (4H, m), 2.16-1.73 (5H, m), 2. 16 (3H, s), 1. 80 (6H, s)

LCMS: m/z 493 [M+H] +

Compound F5-51

6,6,9-Trimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound F5-47, the title compound was prepared from Compound F3-11

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 70 (1H, br. s), 8.33-8. 30 (1H, d, 8. 08 Hz), 8. 00 (1H, s), 7. 95 (1H, s), 7.61-7. 58 (1H, m), 7. 28 (1H, s), 3. 60 (4H, m), 3. 32-3. 26 (2H, m), 2.79-2. 69 (2H, m), 2. 32 (3H, s), 1.95-1. 90 (2H, m), 1. 74 (6H, s), 1. 65-1.52 (2H, m),

LCMS: m/z 469 [M+H] +

Methanesulfonic Acid Salt of Compound F5-51

6,6,9-Trimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile was added with DMSO and 2 N methanesulfonic acid (1.05 eq.) and dissolved therein. After freeze-drying, crystallization was performed with ethanol to obtain methanesulfonic acid salt of 6,6,9-trimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 72 (1H, br. s), 9. 60 (1H, br. s), 8.33-8. 31 (1H, d, 9.8 Hz), 8. 01 (1H, s), 7. 99 (1H, s), 7.61-7. 59 (1H, m), 7. 31 (1H, s), 4.07-4. 04 (2H, m), 3.73-3. 67 (2H, m), 3.55-3. 40 (8H, m), 3.32-3. 26 (1H, m), 2.70-2. 60 (2H, m), 2. 34 (3H, s), 2. 30 (3H, s), 1.95-1.90 (2H, m), 1. 75 (6H, s)

LCMS: m/z 469 [M+H] +

Compound F6-1

9-(1-Isopropyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound F5-36-2 and acetone.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 68 (1H, br. s), 8. 30 (1H, d, 8.1 Hz), 7. 98 (1H, s), 7. 82 (1H, s), 7. 58 (1H, d, 8.1 Hz), 7.20 (1H, s), 5. 85 (1H, s), 3.56-3. 44 (2H, m), 3.21-3. 14 (2H, m), 2.77-2. 66 (5H, m), 2.12-2. 09 (1H, m), 1.98-1. 88 (2H, m), 1. 74 (6H, s), 1.70-1. 63 (1H, m), 1.58-1. 45 (2H, m), 1.09-1. 00 (6H, m)

LCMS: m/z 563 [M+H] +

HPLC retention time: 1.90 min (analysis condition U)

Compound F6-2

9-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A9-1, the title compound was prepared from Compound F5-36-2.

LCMS: m/z 598 [M+H] +

HPLC retention time: 1.52 min (analysis condition S)

Compound F6-3

9-[3-(4-Cyclopropyl-piperazin-1-yl)-propyl]-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-13-1, the title compound was prepared from Compound F5-10.

LCMS: m/z 538 [M+H] +

HPLC retention time: 1.32 min (analysis condition S)

Compound F6-4

9-Ethyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-13-1, the title compound was prepared from Compound F5-16.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 70 (1H, br. s), 8. 29 (1H, d, 8.0 Hz), 8. 03-7. 94 (2H, m), 7.59-7. 55 (1H, m), 7. 38 (1H, s), 4.59-4. 47 (4H, m), 3.53-5. 47 (1H, m), 3.03-2. 97 (2H, m), 2.73-2. 62 (2H, m), 1. 74 (6H, s), 1.29-1. 98 (3H, m)

LCMS: m/z 455 [M+H] +

HPLC retention time: 1.92 min (analysis condition U)

Hydrochloric Acid Salt of Compound F6-4

9-Ethyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile was added with DMSO and 6 N hydrochloric acid (1.05 eq.) and dissolved therein. After freeze-drying, crystallization was performed with ethanol comprising 25% water to obtain monohydrochloric acid salt of 9-ethyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 83 (1H, br. s), 11. 59 (1H, br. s), 8.33-8. 31 (1H, m), 8. 09 (1H, s), 8. 02 (1H, s), 7.63-7. 61 (1H, m), 7. 39 (1H, s), 4.91-4. 60 (4H, br. m), 3.58-3. 40 (1H, m), 3.31-3. 05 (8H, br. m), 2. 73 (2H, q, J=7. 3), 1. 81 (6H, s), 1. 29 (3H, t, J=7. 3)

LCMS: m/z 455 [M+H] +

Compound F6-5

9-(3-Methoxy-propyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-13-1, the title compound was prepared from Compound F5-18.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 73 (1H, br. s), 8.33-8. 30 (1H, d, 8. 08 Hz), 8. 01 (1H, s), 8. 00 (1H, s), 7.62-7. 59 (1H, d, 8.08 Hz), 7. 42 (1H, s), 4.61-4. 56 (2H, m), 4.51-4. 46 (2H, m), 3.53-3. 47 (1H, m), 3.42-3. 37 (2H, m), 3. 02 (4H, m), 2. 75-2. 68 (2H, m), 2. 51 (4H, m), 1.93-1. 82 (2H, m), 1. 76 (6H, s)

LCMS: m/z 499 [M+H] +

Compound F6-6

6,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-9-[3-(4-oxetan-3-yl-piperazin-1-yl)-propyl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-13-1, the title compound was prepared from Compound F5-20.

LCMS: m/z 609 [M+H] +

HPLC retention time: 1.00 min (analysis condition S)

Compound F6-7

9-(2-Cyclopentyl-ethyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-13-1, the title compound was prepared from Compound F5-21.

LCMS: m/z 523 [M+H] +

HPLC retention time: 1.92 min (analysis condition S)

Compound F6-8

6,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-propyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-13-1, the title compound was prepared from Compound F5-22.

1 H-NMR (270 mHz DMSO-d 6 ) δ: 12. 75 (1H, s), 8. 30 (1H, d, J=8.2 Hz), 8. 01-7. 97 (2H, m), 7. 59 (1H, d, J=7.1 Hz), 7. 38 (1H, s), 4. 51 (4H, dt, J=27.7, 6.3 Hz), 3.55-3. 49 (1H, m), 3.02-2. 96 (4H, m), 2.63 (2H, t, J=7.3 Hz), 2.47-2. 41 (4H, m), 1. 73 (6H, s), 1. 70-1. 61 (2H, m), 0.94 (3H, t, J=7.4 Hz).

LCMS: m/z 469 [M+H] +

HPLC retention time: 1.57 min (analysis condition S)

Compound F6-9

8-[4-(4-Hydroxy-butyl)-piperazin-1-yl]-6,6-dimethyl-11-oxo-9-propyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

The title compound was obtained as a by-product of the synthesis of Compound F6-8.

LCMS: m/z 485 [M+H] +

HPLC retention time: 1.61 min (analysis condition S)

Compound F6-10

9-(3-Hydroxy-propyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-13-1, the title compound was prepared from Compound F5-23.

LCMS: m/z 499 [M+H] +

HPLC retention time: 1.42 min (analysis condition S)

Compound F6-11

6,6-Dimethyl-9-(3-morpholin-4-yl-propyl)-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-13-1, the title compound was prepared from Compound F5-26.

LCMS: m/z 554 [M+H] +

HPLC retention time: 1.50 min (analysis condition U)

Compound F6-12

6,6-Dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-9-pentyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-13-1, the title compound was prepared from Compound F5-27.

LCMS: m/z 497 [M+H] +

HPLC retention time: 2.25 min (analysis condition U)

Compound F6-13

9-(3-Isopropoxy-prop-1-ynyl)-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound F5-23 and 2-bromopropane.

1 H-NMR (270 MHz, CD 3 OD+CDCl 3 ) δ: 8. 40 (1H, d, J=7.8 Hz), 8. 32 (1H, s), 7. 84 (1H, s), 7. 53 (1H, d, J=7.8 Hz), 7. 18 (1H, s), 4.80-4. 68 (4H, m), 4. 46 (2H, s), 3. 95 (1H, m), 3. 64 (1H, m), 3. 46 (4H, m), 2. 62 (4H, m), 1. 82 (6H, s), 1. 24 (6H, d, J=7. 0 Hz)

LCMS: m/z 523 [M+H] +

Compound F6-14

9-Isopropyl-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-13-1, the title compound was prepared from Compound F5-32.

1 H-NMR (270 MHz, CD 3 OD+CDCl 3 ) δ: 8. 44 (1H, d, J=7.8 Hz), 8. 27 (1H, s), 7. 84 (1H, s), 7. 54 (1H, d, J=7.8 Hz), 7. 36 (1H, s), 4.82-4. 70 (4H, m), 3. 68 (1H, m), 3. 45 (1H, m), 3.13-3. 09 (4H, m), 2.64-2. 62 (4H, m), 1. 81 (6H, s), 1. 31 (6H, d, J=7. 0 Hz)

LCMS: m/z 469 [M+H] +

Compound F6-15

8-(4-Cyclopropyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-13-1, the title compound was prepared from Compound F5-37.

LCMS: m/z 439 [M+H] +

HPLC retention time: 1.98 min (analysis condition U)

Compound F6-16

8-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-propyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-13-1, the title compound was prepared from Compound F5-38.

LCMS: m/z 453 [M+H] +

HPLC retention time: 1.63 min (analysis condition S)

Compound F6-17

8-(4-Cyclobutyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-13-1, the title compound was prepared from Compound F5-43.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 80 (1H, s), 8. 32 (1H, d, 7.9 Hz), 8. 10 (1H, s), 8. 02 (1H, s), 7. 62 (1H, d, 7.9 Hz), 7. 38 (1H, s), 3.78-3. 88 (1H, m), 3.79-3. 89 (1H, m), 3.48-3. 54 (2H, m), 3.40-3. 47 (2H, m), 3.30-3. 39 (2H, m), 3.02-3. 24 (4H, m), 2. 73 (2H, q, 7.3 Hz), 2.30-2. 41 (2H, m), 2.17-2. 26 (2H, m), 1.71-1. 86 (8H, m), 1. 29 (3H, t, 7.3 Hz)

LCMS: m/z 453 [M+H] +

HPLC retention time: 2.76 min (analysis condition W)

Methanesulfonic Acid Salt of Compound F6-17

8-(4-Cyclobutyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile was dissolved in 6 volumes of DMF at room temperature and added dropwise with aqueous solution of methanesulfonic acid (2 M, 1.05 eq.). The resulting solution was added dropwise to 60 volumes of acetonitrile, and the precipitated solid was filtered and dried to obtain monomethanesulfonic acid salt of 8-(4-cyclobutyl-piperazin-1-yl)-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 75 (1H, s), 8. 31 (1H, J=8.4 Hz), 8. 07 (1H, s), 8. 01 (1H, s), 7. 59 (1H, d, J=7.9 Hz), 7. 38 (1H, s), 3.58-2. 84 (10H, m), 2. 71 (2H, q, J=7.5 Hz), 2. 34 (3H, s), 2.20-2. 04 (4H, m), 1.76-1. 68 (8H, m), 1. 26 (3H, t, J=7.5 Hz)

FABMS: m/z 453 [M+H] +

Compound F6-18

8-(4-Cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-9-propyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-13-1, the title compound was prepared from Compound F5-44.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 69 (1H, s), 8. 31 (1H, d, 7.9 Hz), 8. 01 (1H, s), 7. 99 (1H, s), 7. 60 (1H, d, 7.9 Hz), 7. 39 (1H, s), 2.92-3. 02 (4H, m), 2.75-2. 84 (1H, m), 2. 65 (2H, t, 7.3 Hz), 2.38-2. 48 (4H, m), 1.96-2. 06 (2H, m), 1.78-1. 87 (2H, m), 1. 75 (6H, s), 1.62-1. 73 (4H, m), 0.97 (3H, t, 7.3 Hz)

LCMS: m/z 467 [M+H] +

HPLC retention time: 2.96 min (analysis condition W)

Compound F6-19

8-(4-Cyclobutyl-piperazin-1-yl)-9-isopropyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-13, the title compound was prepared from Compound F5-48.

LCMS: m/z 467 [M+H] +

HPLC retention time: 1.67 min (analysis condition S)

Compound F6-20

9-Ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-13-1, the title compound was prepared from Compound F5-49.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 70 (1H, s), 8. 32 (1H, d, J=7.9 Hz), 8. 04 (1H, s), 8. 00 (1H, s), 7. 61 (1H, d, J=8.5 Hz), 7. 34 (1H, s), 3.64-3. 57 (4H, m), 3.27-3. 18 (2H, m), 2.82-2. 66 (4H, m), 2.39-2.28 (1H, m), 1.96-1. 87 (2H, m), 1. 76 (6H, s), 1. 69-1. 53 (2H, m), 1.29 (3H, t, J=7.3 Hz)

LCMS: m/z 483 [M+H] +

HPLC retention time: 1.98 min (analysis condition U)

Hydrochloric Acid Salt of Compound F6-20

9-Ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile was dissolved in a mixture solution of methylethyl ketone (10 volumes), water (4 volumes) and acetic acid (3 volumes) at 60° C. To the dissolved solution, hydrochloric acid (2 N) was added dropwise (1 volume). After stirring at 60° C. for 30 min, ethanol (25 volume) was added dropwise. The precipitated solid was filtered and dried to obtain monohydrochloric acid salt of 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 78 (1H, s), 10. 57 (1H, br. s), 8. 30 (1H, J=8.4 Hz), 8. 05 (1H, s), 7. 99 (1H, s), 7. 59 (1H, d, J=7.9 Hz), 7. 36 (1H, s), 4.02-3. 99 (2H, m), 3.84-3. 78 (2H, m), 3.51-3. 48 (2H, m), 3.15-3. 13 (1H, s), 2.83-2. 73 (2H, s), 2. 71-2. 67 (2H, s), 2.23-2. 20 (2H, m), 1.94-1. 83 (2H, m), 1. 75 (6H, s), 1. 27 (3H, t, J=7. 5 Hz)

FABMS: m/z 483 [M+H] +

Compound F6-21

6,6-Dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-9-propyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-13-1, the title compound was prepared from Compound F5-50.

1 H-NMR (270 MHz, CD 3 OD+CDCl 3 ) δ: 8. 41 (1H, d, J=7.8 Hz), 8. 14 (1H, s), 7. 84 (1H, s), 7. 53 (1H, d, J=7.8 Hz), 7. 31 (1H, s), 3.77 (4H, m), 3. 32 (2H, m), 2. 86-2. 66 (8H, m), 2.43-2. 05 (3H, m), 1. 79 (6H, s), 1.79-1. 66 (4H, m), 1. 02 (3H, t, J=7.3 Hz)

LCMS: m/z 497 [M+H] +

Compound G2

8-Methoxy-10,10-dimethyl-10,11-dihydro-5H-1,11-diaza-benzo[B]fluorene

2-Hydrazinopyridine (1.3 g, 11.8 mmol) and 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 2.4 g, 11.8 mmol) were dissolved in NMP (60 mL), and stirred at 190° C. for 48 hr. The reaction solution was diluted with ethyl acetate, washed with water and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the target compound (white solid, 101 mg, 3%).

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11. 53 (1H, s), 8.16-8. 12 (1H, m), 7. 84 (1H, d, J=7.8 Hz), 7. 23 (1H, d, J=8.4 Hz), 7. 11 (1H, s), 7.03-6. 98 (1H, m), 6.85-6. 81 (1H, m), 3. 96 (2H, s), 3. 77 (3H, s), 1. 64 (6H, s)

LCMS: m/z 279 [M+H] +

HPLC retention time: 2.08 min (analysis condition U)

Compound G3

8-Methoxy-10,10-dimethyl-10,11-dihydro-1,11-diaza-benzo[b]fluoren-5-one

Under the same conditions as the method for synthesizing Compound A4, the title compound was prepared from Compound G2.

1 H-NMR (400 MHz, CDCl 3 ) δ: 12. 95 (1H, br. s), 8. 78 (1H, d, J=7.8 Hz), 8. 52 (1H, d, J=4.9 Hz), 8. 41 (1H, d, J=8.8 Hz), 7. 37 (1H, dd, J=7.7, 5.0 Hz), 7. 15 (1H, s), 7.04-7. 00 (1H, m), 3. 94 (3H, s), 1. 98 (6H, s)

LCMS: m/z 293 [M+H] +

HPLC retention time: 2.13 min (analysis condition U)

Compound G4

8-Hydroxy-10,10-dimethyl-10,11-dihydro-1,11-diaza-benzo[b]fluoren-5-one

Under the same conditions as the method for synthesizing Compound E3-2, the title compound was prepared from Compound G3.

1 H-NMR (400 MHz, CDCl 3 ) δ: 8. 66 (1H, d, J=7.7 Hz), 8. 29 (1H, d, J=4.9 Hz), 8. 23 (1H, d, J=13.8 Hz), 7. 29 (1H, dd, J=7.7, 5.0 Hz), 7. 12 (1H, s), 6. 93 (1H, d, J=8.6 Hz), 1.71 (6H, s)

LCMS: m/z 279 [M+H] +

HPLC retention time: 1.72 min (analysis condition U)

Compound G5

Trifluoro-methanesulfonic acid 10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluoren-8-yl ester

Under the same conditions as the method for synthesizing Compound B1, the title compound was prepared from Compound G4.

1 H-NMR (400 MHz, CDCl 3 ) δ: 8. 81 (1H, d, J=7.8 Hz), 8.60-8. 52 (2H, m), 7. 55 (1H, s), 7.46-7. 40 (2H, m), 2. 01 (6H, s)

LCMS: m/z 411 [M+H] +

HPLC retention time: 1.75 min (analysis condition U)

Compound G6

10,10-Dimethyl-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-10,11-dihydro-1,11-diaza-benzo[b]fluoren-5-one

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound G5 and 4-pyrrolidin-1-yl-piperidine.

1 H-NMR (400 MHz, CDCl 3 ) δ: 13. 12 (1H, s), 8. 78 (1H, d, J=7.8 Hz), 8. 49 (1H, d, J=4.9 Hz), 8. 29 (1H, d, J=8.8 Hz), 7.34 (1H, dd, J=7.7, 5. 0 Hz), 7.06-6. 98 (2H, m), 3.96-3. 88 (2H, m), 3.02-3. 92 (2H, m), 2.69-2. 60 (4H, m), 2.32-2. 23 (1H, m), 2.09-2. 00 (4H, m), 1. 92 (6H, s), 1.26-1. 19 (4H, m)

LCMS: m/z 415 [M+H] +

HPLC retention time: 1.57 min (analysis condition U)

Compound H1

6-Acetyl-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one

To the dichloromethane (70 ml) solution of 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 3 g, 14.7 mmol), acetic anhydride (1.7 ml, 1.2 eq.) and aluminum chloride-nitrobenzene solution (1 M, 44 ml, 3 eq.) was added at 0° C., and stirred for 3 hr. Thereafter, the reaction solution was added with saturated aqueous solution of sodium hydrogen carbonate and extracted twice with dichloromethane. The organic layer was washed with brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound as a crude product.

Compound H2-1

1-(3-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-ethanone

Under the same conditions as the method for synthesizing Compound A3-1, the title compound was prepared from Compound H1 and (3-bromo-phenyl)-hydrazine.

LCMS: m/z 398 [M+H] +

HPLC retention time: 3.97 min (analysis condition Y)

Compound H2-2

1-(1-Bromo-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-ethanone

The title compound was obtained as a by-product of the synthesis of Compound H2-1.

LCMS: m/z 398 [M+H] +

HPLC retention time: 3.97 min (analysis condition Y)

Compound H3

9-Acetyl-3-bromo-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one

Under the same conditions as the method for synthesizing Compound A4, the title compound was prepared from Compound H2.

1 H-NMR (300 MHz, DMSO-d 6 ) δ: 1. 80 (6H, s), 2. 58 (3H, s), 4. 06 (3H, s), 7. 38 (1H, dd, 8. 39 Hz, 1. 91 Hz), 7. 51 (1H, s), 7. 67 (1H, bs, 1. 53 Hz), 8. 10 (1H, d, 8. 39 Hz), 8. 41 (1H, s), 12. 3 (1H, s)

LCMS: m/z 412, 414 [M+H] +

HPLC retention time: 2.73 min (analysis condition U)

Compound H4

9-Acetyl-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

According to the same method as the method for synthesizing Compound A5-2, the title compound was prepared from Compound H3.

1 H-NMR (300 MHz, DMSO-d 6 ) δ: 1. 83 (6H, s), 2. 58 (3H, s), 4. 07 (3H, s), 7. 53 (1H, s), 7. 61 (1H, d, 8.01 Hz), 8. 03 (1H, s), 8. 31 (1H, d, 8.77 Hz), 8. 42 (1H, s), 12. 8 (1H, s).

LCMS: m/z 359 [M+H] +

HPLC retention time: 2.47 min (analysis condition U)

Compound H5

9-Acetyl-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A6, the title compound was prepared from Compound H4.

1 H-NMR (300 MHz, DMSO-d 6 ) δ: 1. 77 (6H, s), 2. 75 (3H, s), 7. 43 (1H, s), 7. 63 (1H, d, 8.01 Hz), 8. 02 (1H, s), 8. 32 (1H, d, 8.01 Hz), 8. 67 (1H, s), 12. 2 (1H, s), 12. 8 (1H, s).

LCMS: m/z 345 [M+H] +

HPLC retention time: 2.27 min (analysis condition S)

Compound H6-1

9-Acetyl-6,6-dimethyl-11-oxo-8-(tetrahydro-pyran-4-yloxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound H5 and tetrahydropyran-4-ol.

LCMS: m/z 429 [M+H] +

HPLC retention time: 2.48 min (analysis condition U)

Compound H6-2

9-Acetyl-8-(2-diethylamino-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound H5.

LCMS: m/z 444 [M+H] +

HPLC retention time: 2.05 min (analysis condition U)

Compound H7

Trifluoro-methanesulfonic acid 9-acetyl-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester

Under the same conditions as the method for synthesizing Compound B1, the title compound was prepared from Compound H5.

1 H-NMR (300 MHz, DMSO-d 6 ) δ: 1. 83 (6H, s), 2. 74 (3H, s), 7. 68 (1H, dd, 8.01 Hz, 1.53 Hz), 8. 08 (2H, s), 8. 33 (1H, d, 8.77 Hz), 8. 79 (1H, s), 12. 9 (1H, s).

Compound H8-1

9-Acetyl-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound H7 and 4-pyrrolidin-1-yl-piperidine.

1 H-NMR (300 MHz, DMSO-d 6 ) δ: 1. 65 (2H, m), 1. 69 (4H, s), 1. 79 (6H, s), 1.95 (2H, m), 2. 18 (1H, m), 2. 54 (4H, s), 2. 59 (3H, s), 2. 93 (2H, t, 11. 8 Hz), 3. 37 (2H, m), 7. 36 (1H, s), 7. 60 (1H, d, 8. 01), 8. 01 (1H, s), 8. 13 (1H, s), 8. 30 (1H, d, 8. 39), 12. 7 (1H, s).

LCMS: m/z 481 [M+H] +

HPLC retention time: 2.03 min (analysis condition U)

Compound H8-2

9-Acetyl-8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound H7.

LCMS: m/z 455 [M+H] +

HPLC retention time: 2.02 min (analysis condition U)

Compound H8-3

9-Acetyl-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound H7 and morpholine.

LCMS: m/z 414 [M+H] +

HPLC retention time: 2.11 min (analysis condition S)

Compound H8-4

9-Acetyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound H7 and 4-piperidin-4-yl-morpholine.

LCMS: m/z 497 [M+H] +

HPLC retention time: 1.45 min (analysis condition S)

Compound H8-5

9-Acetyl-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound H7 and piperazine.

LCMS: m/z 413 [M+H] +

HPLC retention time: 1.71 min (analysis condition U)

Compound H9-1

9-Acetyl-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound H8-5 and cyclobutanone.

LCMS: m/z 467 [M+H] +

HPLC retention time: 1.82 min (analysis condition U)

Compound H9-2

9-Acetyl-6,6-dimethyl-11-oxo-8-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound H8-5 and tetrahydropyran-4-one.

LCMS: m/z 497 [M+H] +

HPLC retention time: 1.76 min (analysis condition U)

Compound H9-3

9-Acetyl-8-[4-(1,1-dimethyl-prop-2-ynyl)-piperazin-1-yl]-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

To the anhydrous THF solution (0.5 mL) of 9-acetyl-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound H8-5, 25 mg, 0.06 mmol), 3-chloro-3-methyl-but-1-yne (0.013 mL, 0.12 mmol), copper (I) chloride (0.6 mg, 0.006 mmol) and triethylamine (0.017 mL, 0.12 mmol) were added at room temperature. After stirring for 30 min, the mixture was added with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by amino silica gel column chromatography (dichloromethane/methanol) to obtain the title compound (white solid, 9.8 mg, 35%).

LCMS: m/z 479 [M+H] +

HPLC retention time: 1.88 min (analysis condition U)

Compound I1-1

6-Chloro-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one

7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 3.37 g, 16.5 mmol) was dissolved in CH 3 CN (82 mL), added with NCS (2.42 g, 1.1 eq.) and stirred at 90° C. for 1.5 hr. The reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed and the target compound was obtained after concentration under reduced pressure (yellow oily substance, 4.45 g).

1 H-NMR (400 MHz, CDCl 3 ) δ: 7. 16 (1H, s), 6. 85 (1H, s), 3. 90 (3H, s), 3. 00 (2H, t, J=6.8 Hz), 2. 65 (2H, t, J=6.8 Hz), 1. 42 (6H, s).

LCMS: m/z 239 [M+H] +

HPLC retention time: 2.80 min (analysis condition U)

Compound I1-2

9-Chloro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

6-Chloro-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound I1-1, 4.45 g, 16.5 mmol) and 3-hydrazinobenzonitrile (2.63 g, 1.2 eq.) were dissolved in TFA (91 mL), and stirred at 90° C. for 3 hr. According to the concentration under reduced pressure, TFA was removed and the residues were added with saturated aqueous solution of NaHCO 3 , followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were added with ethyl acetate. After stirring at room temperature, the precipitated solid was separated by filtration. The filtrate was concentrated under reduced pressure to obtain the title compound as a mixture with I1-3 (red powder, 6.46 g).

Compound I1-3

9-Chloro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-1-carbonitrile

The title compound was obtained as a by-product of the synthesis of Compound I1-2.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11. 66 (1H, s), 7.65-7. 69 (1H, m), 7.44-7. 48 (1H, m), 7. 39 (1H, s), 7. 29 (1H, s), 7.17-7. 23 (1H, m), 4. 21 (2H, s), 3. 91 (3H, s), 1. 69 (6H, s).

LCMS: m/z 337 [M+H] +

HPLC retention time: 3.15 min (analysis condition U)

Compound I2-1

2-(4-Chloro-3-methoxy-phenyl)-2-methyl-propionitrile

1-Chloro-4-fluoro-2-methoxy-benzene (4.3 g, 26.78 mmol) and isobutyronitrile (9.61 mL, 4.0 eq.) were dissolved in toluene (9.0 mL), added with KHMDS (80 mL, 0.5 M toluene solution) and stirred at 65° C. for 2 hr. The reaction solution was cooled to room temperature, added with aqueous solution of 1 N hydrochloric acid and then extracted with MTBE. The organic layer was washed with saturated brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.72 g, 31%).

1 H-NMR (270 MHz, CDCl 3 ) δ: 7. 37 (1H, d, J=8.4 Hz), 7. 05 (1H, d, J=2.1 Hz), 6. 97 (1H, dd, J=8.2, 2.1 Hz), 3. 95 (3H, s), 1.73 (6H, s).

HPLC retention time: 2.33 min (analysis condition S)

Compound I2-2

4-(4-Chloro-3-methoxy-phenyl)-4-methyl-3-oxo-pentanoic acid ethyl ester

Under the same conditions as the method for synthesizing Compound K3, the title compound was prepared from Compound I2-1.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 7. 42 (1H, d, J=8.1 Hz), 6. 92 (1H, d, J=2.1 Hz), 6. 86 (1H, dd, J=8.2, 2.3 Hz), 4. 01 (2H, q, J=7.1 Hz), 3. 87 (3H, s), 3. 43 (2H, s), 1.44 (6H, s), 1. 12 (3H, t, J=7.2 Hz).

LCMS: m/z 299, 301 [M+H] +

HPLC retention time: 2.52, 3.05 min (analysis condition S)

Compound I2-3

4-(4-Chloro-3-methoxy-phenyl)-2-(4-cyano-2-nitro-phenyl)-4-methyl-3-oxo-pentanoic acid ethyl ester

Under the same conditions as the method for synthesizing Compound K4, the title compound was obtained as a crude product from Compound I2-2.

Compound I2-4

2-[1-(4-Chloro-3-methoxy-phenyl)-1-methyl-ethyl]-6-cyano-1H-indole-3-carboxylic acid ethyl ester

Under the same conditions as the method for synthesizing Compound K5, the title compound was obtained from Compound I2-3.

LCMS: m/z 397, 399 [M+H] +

HPLC retention time: 2.83 min (analysis condition S)

Compound I3

9-Chloro-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

(Method 1) Under the same conditions as the method for synthesizing Compound A4, the title compound was obtained from Compound I1-2.

(Method 2) Under the same conditions as the method for synthesizing Compound L8-1, the title compound was obtained from Compound I2-4.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 79 (1H, s), 8.27-8. 31 (1H, m), 8. 12 (1H, s), 8.00-8. 02 (1H, m), 7.58-7. 63 (1H, m), 7. 51 (1H, s), 4. 03 (3H, s), 1. 80 (6H, s).

LCMS: m/z 351 [M+H] +

HPLC retention time: 2.87 min (analysis condition U)

Compound I4

9-Chloro-8-hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E3-2, the title compound was prepared from Compound I3.

LCMS: m/z 337 [M+H] +

HPLC retention time: 2.47 min (analysis condition U)

Compound I5

Trifluoro-methanesulfonic acid 9-chloro-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester

Under the same conditions as the method for synthesizing Compound B1, the title compound was prepared from Compound I4.

LCMS: m/z 469 [M+H] +

HPLC retention time: 3.40 min (analysis condition U)

Compound I6-1

9-Chloro-6,6-dimethyl-11-oxo-8-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound I5 and 4-pyrrolidin-1-yl-piperidine.

LCMS: m/z 473 [M+H] +

HPLC retention time: 2.25 min (analysis condition U)

Compound I6-2

9-Chloro-8-(4-isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound I5.

LCMS: m/z 447 [M+H] +

HPLC retention time: 2.30 min (analysis condition U)

Compound I6-3

9-Chloro-6,6-dimethyl-8-morpholin-4-yl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from I5 and morpholine.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 79 (1H, s), 8. 28 (1H, d, 8.0 Hz), 8. 09 (1H, s), 8. 00 (1H, s), 7. 59 (1H, d, 8.0 Hz), 7. 45 (1H, s), 3.75-3. 81 (4H, m), 3.13-3. 19 (4H, m), 1.76 (6H, s)

LCMS: m/z 406 [M+H] +

HPLC retention time: 2.88 min (analysis condition U)

Compound I6-4

9-Chloro-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound I5 and 4-piperidin-4-yl-morpholine.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 75 (1H, s), 8. 28 (1H, d, 8.0 Hz), 8. 07 (1H, s), 8. 00 (1H, s), 7. 59 (1H, d, 8.0 Hz), 7. 41 (1H, s), 3.55-3. 62 (4H, m), 3.47-3. 56 (4H, m), 2.75-2. 86 (2H, m), 2.45-2. 55 (4H, m), 2.28-2. 39 (1H, m), 1.86-1. 96 (2H, m), 1. 76 (6H, s), 1.52-1. 66 (2H, m)

LCMS: m/z 489 [M+H] +

HPLC retention time: 1.97 min (analysis condition U)

Compound I6-5-1

[1-(9-Chloro-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound I5 and piperidin-4-yl-carbamic acid tert-butyl ester.

LCMS: m/z 519 [M+H] +

HPLC retention time: 3.27 min (analysis condition U)

Compound I6-5-2

8-(4-Amino-piperidin-1-yl)-9-chloro-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound I6-5-1.

LCMS: m/z 419 [M+H] +

HPLC retention time: 2.12 min (analysis condition U)

Compound I6-6

9-Chloro-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound I5 and piperazine.

LCMS: m/z 405 [M+H] +

HPLC retention time: 1.87 min (analysis condition U)

Compound I7-1

N-[1-(9-Chloro-3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-piperidin-4-yl]-methanesulfonamide

Under the same conditions as the method for synthesizing Compound A9-1, the title compound was prepared from Compound I6-5-2.

LCMS: m/z 497 [M+H] +

HPLC retention time: 2.62 min (analysis condition U)

Compound I7-2

9-Chloro-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound I5 and 1-oxetan-3-yl-piperazine.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 78 (1H, s), 8.27-8. 31 (1H, m), 8.07-8. 09 (1H, s), 7.99-8. 02 (1H, m), 7.59-7. 62 (1H, m), 7.44-7. 46 (1H, s), 4.54-4. 60 (2H, m), 4.44-4. 51 (2H, m), 3.47-3. 55 (1H, m), 3.16-3. 24 (4H, m), 2.40-2. 55 (4H, m), 1. 77 (6H, s)

LCMS: m/z 461 [M+H] +

HPLC retention time: 2.13 min (analysis condition U)

Compound I7-3

9-Chloro-8-(4-cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound I5 and 1-cyclopropylpiperazine.

LCMS: m/z 445 [M+H] +

HPLC retention time: 1.97 min (analysis condition U)

Compound I7-4

9-Chloro-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound I6-6 and cyclobutanone.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 78 (1H, s), 8. 29 (1H, d, 8.5 Hz), 8. 08 (1H, s), 8. 01 (1H, s), 7. 60 (1H, d, 8.5 Hz), 7. 44 (1H, s), 3.17-3. 15 (4H, m), 2.83-2. 76 (1H, m), 2.47-2. 44 (4H, m), 2.04-1. 97 (2H, m), 1. 82 (2H, t, 9.8 Hz), 1. 77 (6H, s), 1. 70-1. 63 (2H, m)

LCMS: m/z 459, 461 [M+H] +

HPLC retention time: 1.63 min (analysis condition S)

Compound J2

6-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one

Under the same conditions as the method for synthesizing Compound A2, the title compound was prepared from 6-methoxy-3,4-dihydro-1H-naphthalen-2-one and iodomethane.

LCMS: m/z 205 [M+H] +

HPLC retention time: 1.54 min (analysis condition S)

Compound J3-1

9-Methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E2-1, the title compound was prepared from Compound J2 and 3-hydrazino-benzonitrile.

LCMS: m/z 303 [M+H] +

HPLC retention time: 2.73 min (analysis condition S)

Compound J3-2

9-Methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole-1-carbonitrile

Compound J3-2 was obtained as a by-product of the synthesis of Compound J3-1.

LCMS: m/z 303 [M+H] +

HPLC retention time: 2.67 min (analysis condition S)

Compound J4

9-Methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A4, the title compound was prepared from Compound J3-1 and Compound J3-2 (mixture).

1 H-NMR (DMSO-d 6 ) δ: 12. 79 (1H, s), 8. 33 (1H, d, J=8.2 Hz), 8. 02 (1H, s), 7. 81 (1H, d, J=8.6 Hz), 7. 69 (1H, d, J=3.0 Hz), 7. 63 (1H, dd, J=8.3, 1.4 Hz), 7. 28 (1H, dd, J=8.7, 3. 0 Hz), 3. 87 (3H, s), 1. 74 (6H, s).

LCMS: m/z 317 [M+H] +

HPLC retention time: 2.25 min (analysis condition S)

Compound J5

9-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A6, the title compound was prepared from Compound J4.

1 H-NMR (DMSO-d 6 ) δ: 12. 75 (1H, s), 9. 77 (1H, s), 8. 32 (1H, dd, J=8.2, 0. 7 Hz), 8. 01 (1H, s), 7. 68 (1H, d, J=8.6 Hz), 7. 62 (1H, dd, J=8.2, 1.4 Hz), 7. 58 (1H, d, J=2.8 Hz), 7. 10 (1H, dd, J=8.6, 2.8 Hz), 1. 72 (6H, s).

LCMS: m/z 303 [M+H] +

HPLC retention time: 1.75 min (analysis condition S)

Compound J6

Trifluoro-methanesulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl ester

Under the same conditions as the method for synthesizing Compound B1, the title compound was prepared from Compound J5.

1 H-NMR (DMSO-d 6 ) δ: 12. 95 (1H, s), 8. 31 (1H, d, J=8.2 Hz), 8. 15 (2H, m), 8. 05 (1H, s), 7. 87 (1H, dd, J=9. 0, 2. 7 Hz), 7. 65 (1H, d, J=8. 2 Hz), 1. 80 (6H, s).

LCMS: m/z 435 [M+H] +

HPLC retention time: 2.75 min (analysis condition S)

Compound J7-1

9-Isopropoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound J4 and isopropanol.

LCMS: m/z 345 [M+H] +

HPLC retention time: 3.87 min (analysis condition W)

Compound J7-2-1

4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl oxy)-piperidine-1-carboxylic acid tert-butyl ester

Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound J5.

LCMS: m/z 486 [M+H] +

HPLC retention time: 4.15 min (analysis condition W)

Compound J7-2-2

6,6-Dimethyl-11-oxo-9-(piperidin-4-yl oxy)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound J7-2-1.

LCMS: m/z 386 [M+H] +

HPLC retention time: 2.48 min (analysis condition W)

Compound J7-2-3

6,6-Dimethyl-9-(1-oxetan-3-yl-piperidin-4-yl oxy)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound J7-2-2 and oxetan-3-one.

LCMS: m/z 442 [M+H] +

HPLC retention time: 2.61 min (analysis condition W)

Compound J7-3

6,6-Dimethyl-11-oxo-9-(4-pyrrolidin-1-yl-piperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-10, the title compound was prepared from Compound J6 and 4-pyrrolidin-1-yl-piperidine.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 13. 12 (1H, s), 8. 32 (1H, d, J=8.1 Hz), 8. 01 (1H, s), 7. 72 (1H, d, J=8. 7 Hz), 7. 68 (1H, d, J=2. 6 Hz), 7. 62 (1H, dd, J=8. 2, 1. 2 Hz), 7. 38 (1H, dd, J=9. 1, 2. 8 Hz), 3.90 (2H, d, J=11. 5 Hz), 2. 76 (2H, t, J=12. 2 Hz), 2. 14 (2H, d, J=10.9 Hz), 1. 91 (4H, br), 1. 74 (6H, s).

LCMS: m/z 439 [M+H] +

HPLC retention time: 1.35 min (analysis condition S)

Compound J7-4

9-(4-Isopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-10, the title compound was prepared from Compound J6 and 1-isopropyl-piperazine.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 12. 80 (1H, s), 8. 33 (1H, d, J=7.6 Hz), 8. 02 (1H, s), 7. 66 (3H, m), 7. 33 (1H, d, J=8.2 Hz), 3. 21 (4H, br), 2. 66 (5H, m), 1.72 (6H, s), 1. 02 (6H, d, J=6. 3 Hz).

LCMS: m/z 413 [M+H] +

HPLC retention time: 1.38 min (analysis condition S)

Compound J7-5

6,6-Dimethyl-11-oxo-9-pyrrolidin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-10, the title compound was prepared from Compound J6 and pyrrolidine.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 24 (1H, d, J=8.1 Hz), 7. 91 (1H, s), 7. 59 (1H, d, J=8. 6 Hz), 7. 45 (1H, d, J=7. 9 Hz), 7. 30 (1H, d, J=2. 6 Hz), 6. 85 (1H, dd, J=8. 6, 2. 8 Hz), 3. 31 (4H, t, J=6. 3 Hz), 1. 99 (4H, t, J=6. 2 Hz), 1. 67 (6H, s).

LCMS: m/z 356 [M+H] +

HPLC retention time: 2.38 min (analysis condition S)

Compound J7-6

6,6-Dimethyl-11-oxo-9-((S)-2-pyrrolidin-1-yl methyl-pyrrolidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-10, the title compound was prepared from Compound J6 and (S)-2-pyrrolidin-1-yl methyl-pyrrolidine.

LCMS: m/z 439 [M+H] +

HPLC retention time: 1.50 min (analysis condition S)

Compound J7-7

6,6-Dimethyl-11-oxo-9-piperazin-1-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-10, the title compound was prepared from Compound J6 and piperazine.

LCMS: m/z 371 [M+H] +

HPLC retention time: 1.31 min (analysis condition S)

Compound J7-8

9-(3-Hydroxy-3-methyl-but-1-ynyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-1, the title compound was prepared from Compound J6.

LCMS: m/z 369 [M+H] +

HPLC retention time: 2.16 min (analysis condition S)

Compound J7-9

9-Ethynyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound E4-2-2, the title compound was prepared from Compound J7-8.

1 H-NMR (270 MHz, DMSO-d 6 ) δ: 8. 31 (1H, d, J=8.1 Hz), 8. 23 (1H, d, J=1. 8 Hz), 8. 02 (1H, d, J=1. 3 Hz), 7. 93 (1H, d, J=8. 2 Hz), 7. 78 (1H, dd, J=8. 2, 1. 8 Hz), 7. 61 (1H, dd, J=8.1, 1.3 Hz), 4. 31 (1H, s), 1.77 (6H, s).

LCMS: m/z 311 [M+H] +

HPLC retention time: 2.40 min (analysis condition S)

Compound J7-10-1

4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

Under the same conditions as the method for synthesizing Compound B2-22-1, the title compound was prepared from Compound J6.

LCMS: m/z 468 [M+H] +

HPLC retention time: 2.90 min (analysis condition S)

Compound J7-10-2

6,6-Dimethyl-11-oxo-9-(1,2,3,6-tetrahydro-pyridin-4-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound A8-1, the title compound was prepared from Compound J7-10-1.

LCMS: m/z 368 [M+H] +

HPLC retention time: 1.27 min (analysis condition S)

Compound J7-11-1

9-(Piperidin-4-ylmethyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B2-25-1 and Compound B2-25-2, the title compound was prepared from Compound J6.

LCMS: m/z 384 [M+H] +

HPLC retention time: 1.42 min (analysis condition S)

Compound J7-11-2

9-(1-Isopropyl-piperidin-4-ylmethyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile

Under the same conditions as the method for synthesizing Compound B3-32, the title compound was prepared from Compound J7-11-1 and acetone.

1 H-NMR (400 MHz, DMSO-d 6 ) δ: 12. 79 (1H, s), 8. 33 (1H, d, 7.9 Hz), 8. 01 (1H, s), 7. 98 (1H, d, 1.8 Hz), 7. 79 (1H, d, 7.9 Hz), 7. 61 (1H, d, 7.9 Hz), 7.51-7. 49 (1H, m), 2. 74 (2H, d, 11. 0 Hz), 2.64-2. 60 (3H, m), 2. 04 (2H, t, 10. 7 Hz), 1.77 (6H, s), 1. 60-1. 51 (3H, m), 1.23-1. 14 (2H, m), 0.94 (6H, d, 6.7 Hz)

LCMS: m/z 426 [M+H] +

Compound J7-12

4-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl oxy)-butyric acid

9-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound J5, 30 mg, 0.099 mmol), 4-bromo-butyric acid methyl ester (24.9 μl, 0.198 mmol) and cesium carbonate (64.5 mg, 0.198 mmol) were dissolved in DMA (0.20 ml) and stirred at room temperature for 4 hr. Water was added to the reaction solution, which was then extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The yellow solid obtained after concentration under reduced pressure was purified by silica gel column chromatography (methylene chloride/MeOH) to obtain 4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yloxy)-butyric acid methyl ester as an intermediate.

The intermediate was dissolved in MeOH (0.50 ml), added with aqueous solution of sodium hydroxide (6 mol/l) and stirred at room temperature for 30 min. The reaction solution was added with hydrochloric acid (3 mol/l), extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, white solid was obtained, which was then washed with methylene chloride to obtain the title compound (19.0 mg, 70%).

LCMS: m/z 389 [M+H] +

HPLC retention time: 2.39 min (analysis condition F)

Compound J7-13

5-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl oxy)-pentanoic acid

Under the same conditions as the method for synthesizing Compound J7-12, Compound J5 and 5-bromo-pentanoic acid methyl ester were reacted to obtain the target compound (19.5 mg, 64%).

LCMS: m/z 403 [M+H] +

HPLC retention time: 2.49 min (analysis condition F)

Compound J7-14

6-(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl oxy)-hexanoic acid

Under the same conditions as the method for synthesizing Compound J7-12, Compound J5 and 6-bromo-hexanoic acid ethyl ester were reacted to obtain the target compound (19.6 mg, 66%).

LCMS: m/z 417 [M+H] +

HPLC retention time: 2.61 min (analysis condition F)