Indole derivative as well as synthesis method and application thereof

[0069] Example 1: 4- (5- (4-aminopiperidine-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indole-1-yl) benzonitrile

[0070]

[0071] Step 1: Synthesis 4-ethynyl-2-fluoro-1-methoxybenzene

[0072]

[0073] 3-fluoro-4-methoxybenzaldehyde (1.0eq), MeOH (1-Net nitrogen-2-oxo-propanol) -phoninic acid dimethyl (2.2 eq), K 2 CO 3 (2.2eq), the reaction was stirred at room temperature overnight. After the reaction is complete, the carnation solvent, column chromatography purification (according to volume gauge, PE: EA = 10: 1, PE means petroleum ether, EA refers to ethyl acetate, the meaning of the following: The compound is a pale yellow oily liquid.

[0074] Step 2: Synthesis 4-bromine-2 - ((4-methoxy-3-methylphenyl) ethynyl) aniline

[0075]

[0076]4-ethynyl-2-fluoro-1-methoxyenzene (1.2eq), 4-bromo-2-iodine aniline (1.0 eq), DMA (dimethylacetamide, CAS login number: 127-19-5), PD (PPH 3 ) 2 CL 2 (0.2eq), Cui (0.2eq), ET 2 N (1.5 eq, ET refers to the ether), and after nitrogen protection, the reaction is stirred at room temperature, and the TLC monitors the reaction process. After the reaction was completed, 100 ml of ethyl acetate was added to the reaction bottle, and then washed with water (100 ml * 5 times, that is, washed 5 times, 100 ml of water each time), and finally washed (100 ml * 1), sodium sulfate sulfate. Dry, filtered, dry solvent, column chromatography (PE: EA = 3: 1), resulting in a brown oil.

[0077] Step 3: Synthesis 4- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-indole-1-yl) benzonitrile

[0078]

[0079] 4-bromine-2 - ((4-methoxy-3-methylphenyl) ethynyl) aniline (1.0eq), 4-iodobenzene (1.5 eq), Pd (OAC) 2 (0.1eq), xantphos (0.2eq, 4,5-dual (diphenylphosphine) -9, 9-dimethyl oxide, CAS login number: 161265-03-8), CS 2 CO 3 (2.0eq), Dioxane (1,4-dioxane), after nitrogen protection, warmed to 110 ° C stirring reaction, TLC monitors the reaction process. After the reaction is complete, add DCM to the reaction bottle (CH 2 CL 2 ) .

[0080] 1H NMR (400MHz, Chloroform-D) δ 7.80 (D, J = 1.9 Hz, 1H), 7.75 (D, J = 1.9 Hz, 1H), 7.73 (Q, J = 1.7 Hz, 1H), 7.35 (D J = 2.0 Hz, 1H), 7.33 (D, J = 1.9 Hz, 1H), 7.30 (DD, J = 8.7, 1.9 Hz, 1H), 7.15 (DT, J = 8.8, 0.7 Hz, 1H), 6.97 (DDD, J = 12.0, 1.8, 0.7 Hz, 1H), 6.89-6.86 (m, 2H), 6.71 (D, J = 0.8 Hz, 1H), 3.90 (s, 3h).

[0081] Step 4: Synthesis 4- (1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indole-5-yl) piperazine-1-carboxylic acid Tert-butyl

[0082]

[0083] Add 4- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-hydrazine-1-yl-1-yl) -1-1H-antidine-1-yl-1-yl-1-yl-1-yl-1-yl-1-yl-phenylphenyl (n-boc piperazine). 1.0eq), PD 2 (DBA) 3 (0.11 eq), calcium carbonate, X-phos (0.22 eq), Dioxane, nitrogen protection, heated to 110 ° C reaction, TLC monitored the reaction process. After the reaction is complete, the reaction solution is filtered, carnamed the filtrate, and the residual column chromatography (according to volume gauge, PE: EA = 3: 2), resulting in a yellow solid. MS-ES: (ESI, POS.ION) M / Z: 471.23 [M + H] +.

[0084] Step 5: Synthesis 4- (2- (3-fluoro-4-methoxyphenyl) -5- (piperazine-1-yl) -1H-indole-1-yl) benzonitrile

[0085]

[0086] Add 4- (1- (4-cyanophenyl) -2- (3-fluorophenyl) -2- (3-fluoro-4-methoxyphenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-hydrazine-5-yl) piperazine-1-carboxus Acid tert-butyl acid, dissolved with DCM (3V), then dripping TFA (1V, TFA refers to trifluoroacetic acid), incorporating, stirring reaction at room temperature, TLC monitors the reaction process. After the reaction is complete, the carnation of the reaction liquid, the residue of the residue is carried out with a methanol of the methanol, and then the solvent is then carried out again, and the residual column chromatography is purified (DCM: MeOH = 10: 1) to give the title compound as a pale yellow solid.

[0087] Example 2: 4- (2- (3-fluoro-4-methoxyphenyl) -5- (4- (methyl amino) piperidine-1-yl) -1H-indole-1-group) Benzonitrile (ie, compound I-2)

[0088]

[0089] Step 1: Synthesis (1- (1- (4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indole-5-yl) piperidine-4-yl (Meth) urethane tert-butyl ester

[0090]

[0091] Add 4- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-hydrazine-1-yl-1-yl-1-yl), tert-butyl methyl (piperidine) -4-yl) urethane (1.0eq), PD 2 (DBA) 3 (0.11 EQ), cesium carbonate (2.0 eq), X-PhOS (0.22 eq), Dioxane, nitrogen protected, heated to 110 ° C, TLC monitors the reaction process. After the reaction is complete, the reaction solution is filtered, the carnoff, the residual column chromatography purification (PE: EA = 3: 2), resulting in a yellow solid. MS-ES: (ESI, POS.ION) M / Z: 499.30 [M + H] +.

[0092] Step 2: 4- (2- (3-fluoro-4-methoxyphenyl) -5- (4- (methyl amino) piperidine-1-yl) -1H-indole-1-yl) benzyl Nitrile

[0093]

[0094] Add (1- (4-cyanobiphenyl) -2- (3-fluoro-4-methoxyphenyl) -1H-indole-5-yl) -1H-indole-5-yl) -1H-indole-5-yl-based) piperidine-4- Base) (meth) urethane tert-butyl ester (1.0eq), dissolved with DCM (3V), then dripping TFA (1V), added, stirred at room temperature, TLC monitors the reaction process. After the reaction is complete, the carnation of the reaction liquid, the residue of the residue is carried out with a methanol of the methanol, and then the solvent is then carried out again, and the residual column chromatography is purified (DCM: MeOH = 10: 1) to give the title compound as a pale yellow solid.

[0095] Example 3: 4- (5- (4-aminopiperidine-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indole-1-yl) -2-hydroxyl group Benzonitrile

[0096]

[0097] Step 1: Synthesis 5-bromo-2-cyanobenzyl tert-butyl carbonate

[0098]

[0099] 4-bromo-2-hydroxybenzonitrile (1.0eq), THF (10V), DMAP (0.2 eq), BOC acid anhydride (1.3 eq, tert-tert-butyl di-tert-butyl die ester), TEA (1.5 eq, three) Ethanolamine), incorporate, stirred at room temperature, TLC monitors the reaction process. After the reaction was complete, ethyl acetate (10V) was added to the reaction bottle, and then the 1N dilute hydrochloric acid tuning system pH = 3, the liquid washed, and the organic phase was washed with saturated salt water, dried over anhydrous sodium sulfate. Purification (PE: E: E: E: E: E: E: E: E: E: E A = 3: 1) obtained the title compound as a colorless oil.

[0100] Step 2: Synthesis 5- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-indole-1-yl) -2-cyanobenzyl tert-butyl carbonate

[0101]

[0102] 4-bromo-2 - ((4-methoxy-3-methylphenyl) ethynyl) aniline (1.0eq), 5-bromo-2-cyanobenzyl tert-butyl carbonate is added to the reaction bottle. (1.5 eq), cesium carbonate (2.0 eq), palladium acetate (0.1 eq), Xantphos (0.2 eq), DMF (10V), after the protection, nitrogen protection, temperature rising to 110 ° C, TLC monitors the reaction process. After the reaction was complete, 100 ml of water and 100 ml of ethyl acetate were added to the reaction bottle, and the mixture was allowed to stand after the mixture, and the organic phase was then washed multiple times (100 ml * 5), and then dried over anhydrous sodium sulfate, dried solvent, The residue was purified (PE: EA = 3: 1) to give the title compound as a pale yellow oil.

[0103] Step 3: Synthesis of tert-butyl (1- (3 - (tert-butoxycarbonyl) oxygen group) -4-cyanophenyl) -2- (3-fluoro-4-methoxyphenyl) ) -1H-indole-5-yl) piperidine-4-yl) urethane

[0104]

[0105] 5- (5-bromo-2- (3-fluoro-4-methoxyphenyl) -1H-hydrazine-1-yl) -2-cyanobenzyl tert-butyl carbonate ( 1.0eq), BOC amine piperidine (1.2eq), PD 2 (DBA) 3 (0.11 EQ), cesium carbonate (2.0 eq), X-PhOS (0.23 eq), DMF (10V), nitrogen protected, heated to 110 ° C reactions, TLC monitored the reaction process. After the reaction was complete, 100 ml of ethyl acetate was added to the reaction bottle, and then washed multiple times (100 ml * 5) with water, and then dried over anhydrous sodium sulfate. After drying solvent, the residual column chromatography was purified (PE: EA = 3) : 1), resulting in the title compound as a yellow solid matter.

[0106] Step 4: Synthesis 4- (5- (4-aminopiperidine-1-yl) -2- (3-fluoro-4-methoxyphenyl) -1H-indole-1-yl) -2-hydroxyl group Benzonitrile

[0107]

[0108] Tert-butyl group (1- (3- ((tert-butoxycarbonyl) oxygen) -4-cyanophenyl group) -2- (3-fluoro-4-methoxybenzene) is added to the reaction bottle Base) -1H-indole-5-yl) piperidine-4-yl) urethane (1.0eq), dissolved with DCM (10V), add TFA (3V), add, stirred at room temperature , TLC monitoring the reactive process. After the reaction is complete, the carnation solvent, the residue of the methanol is adj to 9. The residue was purified again, and the residue was purified by P-TLC (DCM: MeOH = 10: 1) to give the title compound as a yellow solid matter.