A 7-fluoro-5-substituted tryptamine compound and its preparation method and use

Abstract

The present invention discloses a 7-fluoro-5-substituted tryptamine compound, a preparation method and a use thereof. The compound is characterized in that the compound has a 7-fluoro-5-substituted tryptamine of the structural formula shown in formula I or a pharmaceutically acceptable salt, ester or solvate thereof. The preparation method comprises the steps of 1) reacting the compound shown in formula II with iron and ammonium chloride to obtain a compound shown in formula III; 2) reacting the compound shown in formula III with sodium nitrite to obtain a compound shown in formula IV; 3) reacting the compound shown in formula IV with stannous chloride to obtain a compound shown in formula V; 4) reacting the compound shown in formula V with a compound shown in formula VI to obtain a compound shown in formula VII; and 5) reacting the compound shown in formula VII with a compound shown in formula VIII to obtain a compound shown in formula I. The compound has the advantage that the compound can effectively bind to 5-HT by coupling with G protein. 1B It binds to the receptor and inhibits the activity of adenylate cyclase.

Description

Technical Field

[0001] The present invention relates to a tryptamine compound, in particular to a 7-fluoro-5-substituted tryptamine compound and a preparation method and application thereof. Background Art

[0002] Migraine is a neurovascular disease, the third most common disease, with an incidence of 14.7%. Symptoms include moderate to severe headaches, as well as nausea, vomiting, photophobia, and phonophobia, severely impacting patients' quality of life and placing a significant burden on both patients and society. The pathological mechanisms of migraine are currently not fully understood, with theories primarily including the vascular, neurological, and trigeminovascular theories. Low rates of medical consultations, inadequate preventive treatment, and excessive use of analgesics in my country contribute to dissatisfaction with treatment outcomes for nearly half of migraine patients. Therefore, the design and synthesis of novel migraine treatment drugs are of great significance.

[0003] Currently, there are two main types of medications for treating migraines: specific medications, including ergotamines and triptans; and nonspecific medications, including analgesics and nonsteroidal anti-inflammatory drugs. Ergotamines have long been widely used to treat migraines, but they have serious side effects and off-target effects. Clinical practice has confirmed that triptans are one of the most effective drugs for treating acute migraines. As specific treatments for migraine attacks, the efficacy and safety of triptans have been confirmed in large-sample randomized, placebo-controlled clinical trials. The official approval of triptans for the treatment of migraines has opened a new chapter in the acute treatment of migraines.

[0004] The triptans currently on the market include sumatriptan, naratriptan, zolmitriptan, rizatriptan, fluvatriptan, almotriptan and eletriptan. The target of this class of drugs in the body is the 5-HT receptor subtype. 1B and 5-HT 1D , is a receptor agonist. This patent uses tryptamine as the core structure and is based on the target 5-HT 1B The receptor agonist binding pocket is used for targeted design, and new 7-fluoro-5-substituted tryptamine compounds are synthesized, and activity evaluation and structure-activity studies are carried out, which has guiding significance for the development of new anti-migraine small molecule drugs. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a 7-fluoro-5-substituted tryptamine compound which can effectively treat migraine, and a preparation method and use thereof.

[0006] The technical solution adopted by the present invention to solve the above technical problems is: a 7-fluoro-5-substituted tryptamine compound, wherein the compound is a 7-fluoro-5-substituted tryptamine compound having the structural formula shown in Formula I or a pharmaceutically acceptable salt, ester or solvate of the 7-fluoro-5-substituted tryptamine compound having the structural formula shown in Formula I,

[0007]

[0008] Wherein, R1 is hydrogen, fluorine, chlorine, bromine, or iodine; R2 is hydrogen, fluorine, chlorine, bromine, or iodine; and R2 is hydrogen, fluorine, chlorine, bromine, or iodine. The compounds are benzene, toluene, ethylbenzene, propylbenzene, butylbenzene, pentylbenzene, hexylbenzene, fluorobenzene, chlorobenzene, bromobenzene, iodobenzene, phenol, anisole, vinylbenzene, 2-phenylacetonitrile, acetophenone, (trifluoromethyl)benzene, biphenyl, 4-methyl-1,1'-biphenyl, 4-ethyl-1,1'-biphenyl, 4-propyl-1,1'-biphenyl, 4-butyl-1,1'-biphenyl, methane, ethane, propane, isopropyl ether, butane, isobutyl ether, or pentane. , hexane, heptane, octane; R3, R4 are H, methane, ethane, propane, butane, pentane, hexane, heptane, octane; n is a positive integer between 1-3; the pharmaceutically acceptable salt, ester or solvate of the compound represented by the above formula I, wherein the salt is an inorganic acid salt or an organic acid salt, the inorganic acid salt is a salt formed by any one of hydrochloric acid, sulfuric acid and phosphoric acid; the organic acid salt is a salt formed by any one of acetic acid, trifluoroacetic acid, malonic acid, succinic acid, citric acid and p-toluenesulfonic acid.

[0009] The preparation method of the above-mentioned 7-fluoro-5-substituted tryptamine compound comprises the following steps:

[0010] (1) reacting the compound represented by formula II with iron and ammonium chloride to obtain the compound represented by formula III;

[0011] (2) reacting the compound represented by formula III with sodium nitrite to obtain the compound represented by formula IV;

[0012] (3) reacting the compound represented by formula IV with stannous chloride to obtain the compound represented by formula V;

[0013] (4) reacting the compound represented by Formula V with the compound represented by Formula VI to obtain the compound represented by Formula VII;

[0014] (5) reacting the compound represented by formula VII with the compound represented by formula VIII to obtain the compound represented by formula I,

[0015]

[0016] Among them, R1 is hydrogen, fluorine, chlorine, bromine, iodine, benzene, toluene, ethylbenzene, propylbenzene, butylbenzene, pentylbenzene, hexylbenzene, fluorobenzene, chlorobenzene, bromobenzene, iodobenzene, phenol, anisole, vinylbenzene, 2-phenylacetonitrile, acetophenone, (trifluoromethyl)benzene, biphenyl, 4-methyl-1,1'-biphenyl, 4-ethyl-1,1'-biphenyl, 4-propyl-1,1'-biphenyl, 4-butyl-1,1'-biphenyl, methane, ethane, propane, isopropylane, butane, isobutane, pentane, hexane, heptane, octane; R2 is hydrogen, fluorine, chlorine, bromine, iodine; R3 and R4 are H, methane, ethane, propane, butane, pentane, hexane, heptane, octane; n is a positive integer between 1 and 3.

[0017] Step (1) is specifically as follows: at 0-100° C., using iron as a reducing agent, reacting the compound represented by formula II with iron and ammonium chloride in anhydrous ethanol at a molar ratio of 1:5:3 for 1-12 hours to obtain the compound represented by formula III.

[0018] Step (2) is specifically as follows: reacting the compound represented by formula III with sodium nitrite at -20-20° C. for 0.5-5 hours to obtain a solution of the compound represented by formula IV.

[0019] Step (3) is specifically as follows: reacting the compound represented by formula IV with stannous chloride at -20-20°C for 1-5 hours to obtain the compound represented by formula V.

[0020] Step (4) is specifically as follows: reacting the compound represented by formula V with the compound represented by formula VI in a 4% sulfuric acid solution at 60-100° C. for 2-12 hours to obtain the compound represented by formula VII.

[0021] Step (5) is specifically as follows: reacting the compound represented by Formula VII and the compound represented by Formula VIII with [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride and potassium phosphate in a 1,4-dioxane solution at 80-100°C for 6-12 hours to obtain the compound represented by Formula I.

[0022] Use of the above 7-fluoro-5-substituted tryptamine compounds in the preparation of drugs for treating migraine.

[0023] Compared with the prior art, the advantages of the present invention are: the present invention provides a 7-fluoro-5-substituted tryptamine compound and its preparation method and use, the compound can effectively bind to 5-HT by coupling with G protein. 1B Receptors (5-HT 1B R) binding, thereby inhibiting the activity of adenylate cyclase. The compounds provided by the present invention have been 1B The raw materials of the compound provided by the present invention are easy to obtain and the preparation method is simple. A series of 5-HT1B The novel small molecule agonist with a target receptor has been shown to have an effect on 5-HT 1B R has good in vitro activity and binding affinity, and has good application prospects in the design and development of anti-migraine drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 Compounds 6 and 11 have a significant effect on 5-HT 1B The EC of compound 6 was 50 =10.77 nM, EC of compound 11 50 =8.57nM;

[0025] Figure 2 Compounds 6 and 11 have a significant effect on 5-HT 1B The binding activity test data of compound 6 i =36.95 nM, K of compound 11 i =16.56nM. DETAILED DESCRIPTION

[0026] The present invention will be described in further detail below with reference to the accompanying drawings and embodiments.

[0027] The examples described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. Where specific techniques or conditions are not specified in the examples, the techniques or conditions described in the literature in this area or in accordance with the product specifications are used. The reagents or instruments used are not specified as manufacturers and are all conventional products that can be obtained commercially. In this article, "compound shown in formula N" is sometimes also referred to as "compound N" in this article, and N is any integer from 1 to 17 in this article, such as "compound shown in formula 2" may also be referred to as "compound 2" in this article. Specific embodiment 1

[0029] A 7-fluoro-5-substituted tryptamine compound, which is a compound having the structural formula shown in Formula I or a pharmaceutically acceptable salt, ester or solvate of the compound having the structural formula shown in Formula I,

[0030]

[0031]

[0032] Among them, R1 is hydrogen, fluorine, chlorine, bromine, or iodine; R2 is hydrogen, fluorine, chlorine, bromine, iodine, benzene, toluene, ethylbenzene, propylbenzene, butylbenzene, pentylbenzene, hexylbenzene, fluorobenzene, chlorobenzene, bromobenzene, iodobenzene, phenol, anisole, vinylbenzene, 2-phenylacetonitrile, acetophenone, (trifluoromethyl)benzene, biphenyl, 4-methyl-1,1'-biphenyl, 4-ethyl-1,1'-biphenyl, 4-propyl-1,1'-biphenyl, 4-butyl-1,1'-biphenyl, methane, ethane, propane, isopropylane, butane, isobutane, pentane, hexane, heptane, or octane; R3 and R4 are H, methane, ethane, propane, butane, pentane, hexane, heptane, or octane; and n is a positive integer between 1 and 3. The pharmaceutically acceptable salts, esters or solvates of the compound represented by the above formula I, wherein the salt is an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is a salt formed by any one of hydrochloric acid, sulfuric acid and phosphoric acid; and the organic acid salt is a salt formed by any one of acetic acid, trifluoroacetic acid, malonic acid, succinic acid, citric acid and p-toluenesulfonic acid.

[0033]

[0034] The 7-fluoro-5-substituted tryptamine compound represented by the above formula I is preferably any one of the following:

[0035] The compound can effectively inhibit the activity of adenylate cyclase by coupling with G protein. 1B The raw materials of the compound provided by the present invention are easy to obtain and the preparation method is simple. A series of 5-HT 1B The invention relates to a novel small molecule agonist targeting a receptor. Experiments have shown that the compound of the invention has a potential anti-migraine effect. Specific embodiment 2

[0037] The preparation method of the 7-fluoro-5-substituted tryptamine compound in the above-mentioned specific embodiment 1 comprises the following steps:

[0038] (1) reacting the compound represented by Formula II with iron and ammonium chloride to obtain the compound represented by Formula III. According to an embodiment of the present invention, the conditions for reacting the compound represented by Formula II with the compound represented by iron and ammonium chloride are not particularly limited, but can also be specifically: reacting the compound represented by Formula II with iron and ammonium chloride in anhydrous ethanol at a molar ratio of 1:5:3 at 0-100° C. for 1-12 hours using iron as a reducing agent to obtain the compound represented by Formula III. This is beneficial to improving the reaction efficiency, reducing side reactions, and increasing the yield.

[0039] (2) reacting the compound represented by Formula III with sodium nitrite to obtain the compound represented by Formula IV. Specifically, the compound represented by Formula III is reacted with sodium nitrite at -20°C to 20°C for 0.5 to 5 hours to obtain a solution of the compound represented by Formula IV. Thus, the reaction can be carried out under the most suitable conditions, which is beneficial to improving the reaction efficiency, reducing side reactions, and increasing the yield.

[0040] (3) reacting the compound represented by Formula IV with stannous chloride to obtain the compound represented by Formula V. Specifically, the compound represented by Formula IV is reacted with stannous chloride at -20°C to 20°C for 1 to 5 hours to obtain the compound represented by Formula V. This method is beneficial for improving reaction efficiency, reducing side reactions, and increasing yield.

[0041] (4) reacting the compound represented by Formula V with the compound represented by Formula VI to obtain the compound represented by Formula VII. Specifically, the compound represented by Formula V and the compound represented by Formula VI are reacted in a 4% sulfuric acid solution at 60-100° C. for 2-12 hours to obtain the compound represented by Formula VII. This method is beneficial for improving reaction efficiency, reducing side reactions, and increasing yield.

[0042] (5) reacting the compound represented by Formula VII with the compound represented by Formula VIII to obtain the compound represented by Formula I. Specifically, the compound represented by Formula VII and the compound represented by Formula VIII are reacted with [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride and potassium phosphate in a 1,4-dioxane solution at 80-100° C. for 6-12 hours to obtain the compound represented by Formula I. Thus, the reaction can be carried out under the most suitable conditions, which is beneficial to improving the reaction efficiency, reducing side reactions, and increasing the yield.

[0043] Wherein, R1 is H, fluorine, chlorine, bromine, or iodine; R2 is H, fluorine, chlorine, bromine, or iodine; R3 and R4 are H, methane, ethane, propane, butane, pentane, hexane, heptane, or octane; and n is a positive integer between 1 and 3. The above-mentioned compound can be prepared quickly and efficiently using the above-mentioned preparation method, and the method is simple to operate, convenient, and suitable for large-scale production.

[0044] Example 1: Preparation of (Compound 1)

[0045] 1. Preparation of 4-bromo-2-fluoroaniline

[0046] 4-Bromo-2-fluoro-1-nitrobenzene (4.57 mmol) and reduced iron powder (22.85 mmol) were added to 10 mL of anhydrous ethanol and stirred at 60° C. for 20 minutes before adding aqueous ammonium chloride solution (1.5 mmol). The reaction was completed by TLC (developing solvent: petroleum ether / ethyl acetate = 20 / 1). The resulting reaction mixture was then filtered through celite while hot. The filtrate was added to 15 mL of water and basified to 7-8° C. with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (3×20 mL). The organic phase was washed with brine and water, then dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation. A white solid powder, i.e., 4-bromo-2-fluoroaniline, was obtained by column chromatography (petroleum ether / ethyl acetate = 20 / 1) with a yield of 70%. The compound structure data are as follows: 1 H NMR (600MHz, DMSO-d6) δ7.22 (dd, J = 11.1, 2.2 Hz, 1H), 7.03 (ddd, J = 8.5, 2.1, 0.8 Hz, 1H), 6.71 (dd, J = 9.6, 8.6 Hz, 1H), 5.32 (s, 2H).

[0047] 2. Preparation of diazo solution

[0048] The 4-bromo-2-fluoroaniline (7.30 mmol) obtained in step 1 was dissolved in acetic acid (5 mL), and 15 mL of concentrated hydrochloric acid was added. The mixture was maintained below 0°C, and an aqueous sodium nitrite solution (10.95 mmol of sodium nitrite was added to 3 mL of water) was added dropwise over 20 minutes to give a clear yellow solution. The solution was directly used for the next step without purification.

[0049] 3. Preparation of (4-bromo-2-fluorophenyl)hydrazine hydrochloride

[0050] The diazo solution from step 2 was added to a stannous chloride hydrochloric acid solution (21.9 mmol of stannous chloride was added to 5 mL of concentrated hydrochloric acid) over half an hour. Stirring was continued at 0°C for 2 hours. The precipitate was washed with brine (10 mL) and the resulting solid was dried under vacuum to obtain a white solid powder, i.e., (4-bromo-2-fluorophenyl)hydrazine hydrochloride. The total yield of the two steps was 64%. The compound structure data is characterized as follows: 1 H NMR (600MHz, Deuterium Oxide) δ7.44 (dd, J=10.9, 2.2Hz, 1H), 7.37 (dt, J=8.6, 1.7Hz, 1H), 7.05 (t, J=8.8Hz, 1H).

[0051] 4. Preparation of N,N-dimethyl-5-bromo-1H-indole-3-ethylamine

[0052] Under a nitrogen atmosphere, a 4% aqueous sulfuric acid solution (10 mL) was heated to 50°C for 30-60 minutes. (4-Bromo-2-fluorophenyl)hydrazine hydrochloride (7.35 mmol) obtained in step 3 was then added to the solution. 4-Dimethylaminobutyraldehyde dimethyl acetal (8.83 mmol) was then added to the solution over half an hour, and the mixture was heated under reflux for 12 hours. TLC (developing solvent: petroleum ether / ethyl acetate = 5 / 1) indicated the reaction was complete. The reactants were cooled to room temperature, and 30% ammonium hydroxide solution (10 mL) was added over half an hour. The product was extracted with ethyl acetate (3 × 10 mL), and the solvent was removed by vacuum concentration. Chromatography (petroleum ether / ethyl acetate = 6 / 1-4 / 1) yielded a white solid powder, N,N-dimethyl-5-bromo-1H-indole-3-ethylamine, with a yield of 50% and a melting point of 124.3-124.8°C. The compound's structural data are as follows: 1 H NMR (600MHz, DMSO-d6) δ11.55(s,1H),7.55(d,J=1.8Hz,1H),7.29(d,J=1.8Hz,1H) ,7.13(dd,J=10.8,1.8Hz,1H),2.80–2.77(m,2H),2.50-2.47(m,2H),2.20(s,6H). 13 C NMR (151MHz, DMSO-d6) δ148.80 (d, J = 249.2Hz), 132.28 (d, J = 7.5Hz), 125.35, 122.83 (d, J = 13. 59Hz), 117.20, 113.92, 109.31 (d, J = 7.6Hz), 109.00 (d, J = 19.6Hz), 59.72, 45.17 (2C), 22.74.

[0053] 5. Preparation of Compound 1

[0054] Under heating conditions of 80°C, N,N-dimethyl-5-bromo-1H-indole-3-ethylamine (0.7 mmol), phenylboronic acid (0.78 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (0.03 mmol), and potassium phosphate (2.11 mmol) obtained in step 4 were heated to reflux overnight in 4 mL of 1,4-dioxane. TLC detection (developing solvent: petroleum ether / ethyl acetate = 1 / 1) was performed. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through celite, and extracted with ethyl acetate. Chromatography (petroleum ether / ethyl acetate = 2 / 1-1 / 1) gave an orange-red solid powder, namely compound 1, with a yield of 70% and a melting point of 123.4-125.9°C. The compound structure data are characterized as follows: 1H NMR(600MHz,DMSO-d6)δ11.36(s,1H),7.70-7.69(m,2H),7.61(s,1H),7.46-7.43(m,2H),7.33-7.3 0(m,1H),7.25(d,J=2.4,1H),7.24-7.21(m,1H),2.88-2.85(m,2H),2.55-2.52(m,2H),2.22(s,6H). 13 C NMR (151MHz, DMSO-d6) δ149.40 (d, J = 243.11Hz), 140.79, 131.75 (d, J = 7.55Hz), 131.55 (d, J = 6.04Hz), 128.85 (2C), 126.82 (2C) ,126.63,124.51,123.28(d,J=13.59Hz),114.55,112.57,105.01(d,J=18.12Hz),59.89,45.21(2C),22.97.HR-MS(ESI):Calcd for[M+H] + :283.1679;Found:283.1611.

[0055] Example 2: (Preparation of Compound 2)

[0056] 1. Preparation of 4-bromo-2-fluoroaniline

[0057] 4-Bromo-2-fluoroaniline was prepared according to Example 1, Step 1.

[0058] 2. Preparation of diazo solution

[0059] Prepare diazo solution according to step 2 of Example 1.

[0060] 3. Preparation of (4-bromo-2-fluorophenyl)hydrazine

[0061] (4-Bromo-2-fluorophenyl)hydrazine was prepared according to Step 3 of Example 1.

[0062] 4. Preparation of N,N-dimethyl-5-bromo-1H-indole-3-ethylamine

[0063] N,N-Dimethyl-5-bromo-1H-indole-3-ethylamine was prepared according to Step 4 of Example 1.

[0064] 5. Preparation of Compound 2

[0065] Compound 2 was prepared according to Step 5 of Example 1, except that the phenylboronic acid in Step 5 of Example 1 was replaced with tolylboronic acid. The resulting compound was a white solid with a yield of 90% and a melting point of 139.3-140.8°C. The compound's structural data are as follows: 1 H NMR(600MHz,DMSO-d6)δ11.32(s,1H),7.59-7.58(m,3H),7.25-7.24(m,3H),7.18(dd ,J=12.6,1.2Hz,1H),2.87–2.84(m,2H),2.54–2.52(m,2H),2.34(s,3H),2.21(s,6H). 13 C NMR(151MHz, DMSO-d6)δ149.37(d,J=243.11Hz),137.91,135.78,131.73(d,J=6.04Hz),131.50(d,J=4.53Hz),129.44(2C),126.62 (2C),124.43,123.11(d,J=13.59Hz),114.45,112.18,104.85(d,J=16.61Hz),59.88,45.20(2C),22.97,20.64.HR-MS(ESI):Calcd for[M+H] + :297.1839;Found:297.1767.

[0066] Example 3: Preparation of (Compound 3)

[0067] 1. Preparation of 4-bromo-2-fluoroaniline

[0068] 4-Bromo-2-fluoroaniline was prepared according to Step 1 of Example 1.

[0069] 2. Preparation of diazo solution

[0070] Prepare diazo solution according to step 2 of Example 1.

[0071] 3. Preparation of (4-bromo-2-fluorophenyl)hydrazine

[0072] (4-Bromo-2-fluorophenyl)hydrazine was prepared according to Step 3 of Example 1.

[0073] 4. Preparation of N,N-dimethyl-5-bromo-1H-indole-3-ethylamine

[0074] N,N-Dimethyl-5-bromo-1H-indole-3-ethylamine was prepared according to Step 4 of Example 1.

[0075] 5. Preparation of Compound 3

[0076] Compound 3 was prepared according to Step 5 of Example 1, except that the phenylboronic acid in Step 5 of Example 1 was replaced with biphenylboronic acid. The resulting compound was a white solid with a yield of 69% and a melting point of 151.7-153.2°C. The compound's structural data are as follows: 1 H NMR(600MHz,DMSO-d6)δ11.38(s,1H),7.82–7.80(m,2H),7.75–7.71(m,4H),7.69(s,1H),7.50-7.47(m,2H),7.39–7.3 6(m,1H),7.31-7.28(dd,J=12.6,1.2Hz,1H),7.27(d,J=1.8Hz,1H),2.90–2.87(m,2H),2.57–2.54(m,2H),2.23(s,6H). 13 C NMR(151MHz,DMSO-d6)δ149.45(d,J=243.11Hz),139.81,139.76,138.33, 131.79(d,J=6.04Hz),130.92(d,J=6.04Hz),129.00(2C),127.41,127.28( 2C),127.09(2C),126.52(2C),124.57,123.37(d,J=15.10Hz),114.60,11 2.52,104.89(d,J=16.61Hz),59.88,45.20(2C),22.97.HR-MS(ESI):Calcd for[M+H] + 359.1904;Found:359.1924.

[0077] Example 4: Preparation of (Compound 4)

[0078] 1. Preparation of 4-bromo-2-fluoroaniline

[0079] 4-Bromo-2-fluoroaniline was prepared according to Step 1 of Example 1.

[0080] 2. Preparation of diazo solution

[0081] Prepare diazo solution according to step 2 of Example 1.

[0082] 3. Preparation of (4-bromo-2-fluorophenyl)hydrazine

[0083] (4-Bromo-2-fluorophenyl)hydrazine was prepared according to Step 3 of Example 1.

[0084] 4. Preparation of N,N-dimethyl-5-bromo-1H-indole-3-ethylamine

[0085] N,N-Dimethyl-5-bromo-1H-indole-3-ethylamine was prepared according to Step 4 of Example 1.

[0086] 5. Preparation of Compound 4

[0087] Compound 4 was prepared according to Step 5 of Example 1, except that chlorophenylboronic acid was used instead of phenylboronic acid in Step 5 of Example 1. The resulting compound was a white solid with an 81% yield and a melting point of 129.0-129.7°C. The compound's structural data are as follows: 1 H NMR(600MHz,DMSO-d6)δ11.39(s,1H),7.74-7.73(m,2H),7.64(s,1H),7.49-7.48(m,2H),7.26(d ,J=1.8Hz,1H),7.24(dd,J=12.6,1.2Hz,1H),2.87–2.85(m,2H),2.55–2.52(m,2H),2.21(s,6H). 13 C NMR(151MHz,DMSO-d6)δ149.40(d,J=243.11Hz),139.60,131.79,131.41,130.11,128.74(2C),128.52(2 C),124.66,123.47,114.68,112.71,104.90(d,J=16.61Hz),59.84,45.20(2C),22.92.HR-MS(ESI):Calcd for[M+H] + 317.1267;Found:317.1221.

[0088] Example 5: Preparation of (Compound 5)

[0089] 1. Preparation of 4-bromo-2-fluoroaniline

[0090] 4-Bromo-2-fluoroaniline was prepared according to Example 1, Step 1.

[0091] 2. Preparation of diazo solution

[0092] Prepare diazo solution according to step 2 of Example 1.

[0093] 3. Preparation of (4-bromo-2-fluorophenyl)hydrazine

[0094] (4-Bromo-2-fluorophenyl)hydrazine was prepared according to Step 3 of Example 1.

[0095] 4. Preparation of N,N-dimethyl-5-bromo-1H-indole-3-ethylamine

[0096] N,N-Dimethyl-5-bromo-1H-indole-3-ethylamine was prepared according to Step 4 of Example 1.

[0097] 5. Preparation of Compound 5

[0098] Compound 5 was prepared according to Step 5 of Example 1, except that the phenylboronic acid in Step 5 of Example 1 was replaced with (4-ethylphenyl)boronic acid. The resulting compound was a white solid with a yield of 76% and a melting point of 123.1-123.7°C. The compound's structural data are as follows: 1 H NMR (600MHz, DMSO-d6) δ11.33(s,1H),7.61-7.60(m,2H),7.58(s,1H),7.27(d,J=7.8Hz,2H),7.24(d,J=2.4Hz,1 H),7.20(m,1H),2.88–2.85(m,2H),2.63(q,J=7.6Hz,2H),2.57–2.54(m,2H),2.23(s,6H),1.21(t,J=7.8Hz,3H). 13 C NMR(151MHz, DMSO-d6)δ149.38(d,J=241.60Hz),142.18,138.23,131.72(d,J=6.04Hz),131.59(d,J=6.04Hz),128.26(2C),126.74(2C ),124.47,123.14(d,J=13.59Hz),114.34,112.27,104.91(d,J=16.61Hz),59.80,45.12(2C),27.79,22.90,15.73.HR-MS(ESI):Calcd for[M+H] + 311.1982;Found:311.1924.

[0099] Example 6: Preparation of (Compound 6)

[0100] 1. Preparation of 4-bromo-2-fluoroaniline

[0101] 4-Bromo-2-fluoroaniline was prepared according to Step 1 of Example 1.

[0102] 2. Preparation of diazo solution

[0103] Prepare diazo solution according to step 2 of Example 1.

[0104] 3. Preparation of (4-bromo-2-fluorophenyl)hydrazine

[0105] (4-Bromo-2-fluorophenyl)hydrazine was prepared according to Step 3 of Example 1.

[0106] 4. Preparation of N,N-dimethyl-5-bromo-1H-indole-3-ethylamine

[0107] N,N-Dimethyl-5-bromo-1H-indole-3-ethylamine was prepared according to Step 4 of Example 1.

[0108] 5. Preparation of Compound 6

[0109] Compound 6 was prepared according to Step 5 of Example 1, except that the phenylboronic acid in Step 5 of Example 1 was replaced with (4-hydroxyphenyl)boronic acid. The resulting compound was a white solid with a yield of 69% and a melting point of 95.8-97.3°C. The compound's structural data are as follows: 1 H NMR(600MHz,DMSO-d6)δ11.26(s,1H),9.44(s,1H),7.50-7.49(m,3H),7.21(d,J=1.8Hz,1H),7.1 2(dd,J=13.2,1.2Hz,1H),6.84-6.82(m,2H),2.85–2.83(m,2H),2.54–2.51(m,2H),2.21(s,6H). 13 C NMR(151MHz,DMSO-d6)δ156.48,149.34(d,J=243.11Hz),131.82,131.76(d,J=6.04Hz),131.68(d,J=6.04Hz),127.82(2C),124 .29,122.73(d,J=13.59Hz),115.63(2C),114.27,111.55,104.67(d,J=16.61Hz),59.90,45.21(2C),23.00.HR-MS(ESI):Calcd for[M+H] + 299.1616;Found:299.1560.

[0110] Example 7: Preparation of (Compound 7)

[0111] 1. Preparation of 4-bromo-2-fluoroaniline

[0112] 4-Bromo-2-fluoroaniline was prepared according to Example 1, Step 1.

[0113] 2. Preparation of diazo solution

[0114] Prepare diazo solution according to step 2 of Example 1.

[0115] 3. Preparation of (4-bromo-2-fluorophenyl)hydrazine

[0116] (4-Bromo-2-fluorophenyl)hydrazine was prepared according to Step 3 of Example 1.

[0117] 4. Preparation of N,N-dimethyl-5-bromo-1H-indole-3-ethylamine

[0118] N,N-Dimethyl-5-bromo-1H-indole-3-ethylamine was prepared according to Step 4 of Example 1.

[0119] 5. Preparation of Compound 7

[0120] Compound 7 was prepared according to Step 5 of Example 1, except that propylboronic acid was used instead of phenylboronic acid. The resulting compound was a white solid with a yield of 23% and a melting point of 119.9-121.3°C. The compound's structural data are as follows: 1 H NMR (600MHz, DMSO-d6) δ11.11(s,1H),7.15(d,J=2.4Hz,1H),7.10(s,1H),6.75-6.72(m,1H),2.78–2.76(m,2H ),2.61(t,J=7.6Hz,2H),2.49-2.48(m,2H),2.20(s,6H),1.60(dt,J=14.7,7.4Hz,2H),0.90(t,J=7.3Hz,3H). 13 CNMR(151MHz,DMSO-d6)δ148.93(d,J=243.11Hz),132.83(d,J=6.04Hz),131.22(d,J=6.04Hz),123.73,122.27(d,J= 12.08Hz),113.44,113.42,106.43(d,J=15.10Hz),59.85,45.17(2C),37.36,24.69,23.04,13.67.HR-MS(ESI):Calcd for[M+H] + 249.1810;Found:249.1767.

[0121] Example 8: Preparation of (Compound 8)

[0122] 1. Preparation of 4-bromo-2-fluoroaniline

[0123] 4-Bromo-2-fluoroaniline was prepared according to Example 1, Step 1.

[0124] 2. Preparation of diazo solution

[0125] Prepare diazo solution according to step 2 of Example 1.

[0126] 3. Preparation of (4-bromo-2-fluorophenyl)hydrazine

[0127] (4-Bromo-2-fluorophenyl)hydrazine was prepared according to Step 3 of Example 1.

[0128] 4. Preparation of N,N-dimethyl-5-bromo-1H-indole-3-ethylamine

[0129] N,N-Dimethyl-5-bromo-1H-indole-3-ethylamine was prepared according to Step 4 of Example 1.

[0130] 5. Preparation of Compound 8

[0131] Compound 8 was prepared according to Step 5 of Example 1, except that the phenylboronic acid in Step 5 of Example 1 was replaced with (4-methoxyphenyl)boronic acid. The resulting compound was a white solid with a yield of 63% and a melting point of 165.4-166.0°C. The compound's structural data are as follows: 1 H NMR (600M-Hz, DMSO-d6) δ11.29 (s, 1H), 7.63-7.62 (m, 2H), 7.54 (s, 1H), 7.23 (d, J = 2.4Hz, 1H), 7.1 8-7.15(m,1H),7.01-7.00(m,2H),3.79(s,3H),2.87–2.84(m,2H),2.55–2.52(m,2H),2.22(s,6H). 13 C NMR (151MHz, DMSO-d6) δ158.32, 149.35 (d, J = 241.6Hz), 133.26, 131.73 (d, J = 6.04Hz), 131.33 (d, J = 6.04Hz), 127.82 (2C), 124.36 ,122.89(d,J=13.59Hz),114.36,114.25(2C),111.87,104.76(d,J=16.61Hz),59.88,55.15,44.19(2C),22.97.HR-MS(ESI):Calcd for[M+H] + 313.1732; Found:313.1716.HR-MS(ESI):Calcd for[M+H] + 313.1732;Found:313.1716.

[0132] Example 9: Preparation of (Compound 9)

[0133] 1. Preparation of 4-bromo-2-fluoroaniline

[0134] 4-Bromo-2-fluoroaniline was prepared according to Example 1, Step 1.

[0135] 2. Preparation of diazo solution

[0136] Prepare diazo solution according to step 2 of Example 1.

[0137] 3. Preparation of (4-bromo-2-fluorophenyl)hydrazine

[0138] (4-Bromo-2-fluorophenyl)hydrazine was prepared according to Step 3 of Example 1.

[0139] 4. Preparation of N,N-dimethyl-5-bromo-1H-indole-3-ethylamine

[0140] N,N-Dimethyl-5-bromo-1H-indole-3-ethylamine was prepared according to Step 4 of Example 1.

[0141] 5. Preparation of Compound 9

[0142] Compound 9 was prepared according to Step 5 of Example 1, except that the phenylboronic acid in Step 5 of Example 1 was replaced with (4-vinylphenyl)boronic acid. The resulting compound was a white solid with an 83% yield and a melting point of 92.0-93.0°C. The compound's structural data are as follows: 1 H NMR (600MHz, DMSO-d6) δ11.36 (s, 1H), 7.70 (d, J = 8.4Hz, 2H), 7.64 (s, 1H), 7.54 -7.53(m,2H),7.26–7.24(m,2H),6.77(dd,J=17.4,10.8Hz,1H),5.86(d,J=17.7H z,1H),5.27(d,J=11.4Hz,1H),2.88–2.86(m,2H),2.55–2.53(m,2H),2.22(s,6H). 13 CNMR(151MHz,DMSO-d6)δ149.54(d,J=243.11Hz),140.21,136.29,135.44,131.75(d,J=7.55Hz),130.98(d,J=6.04Hz),126.87(2C),12 6.64(2C),124.52,123.33(d,J=13.59Hz),114.60,113.92,112.42,104.83(d,J=16.61Hz),59.86,45.19(2C),22.95.HR-MS(ESI):Calcd for[M+H] + 309.1815;Found:309.4084.

[0143] Example 10: Preparation of (Compound 10)

[0144] 1. Preparation of 4-bromo-2-fluoroaniline

[0145] 4-Bromo-2-fluoroaniline was prepared according to Example 1, Step 1.

[0146] 2. Preparation of diazo solution

[0147] Prepare diazo solution according to step 2 of Example 1.

[0148] 3. Preparation of (4-bromo-2-fluorophenyl)hydrazine

[0149] (4-Bromo-2-fluorophenyl)hydrazine was prepared according to Step 3 of Example 1.

[0150] 4. Preparation of N,N-dimethyl-5-bromo-1H-indole-3-ethylamine

[0151] N,N-Dimethyl-5-bromo-1H-indole-3-ethylamine was prepared according to Step 4 of Example 1.

[0152] 5. Preparation of Compound 10

[0153] Compound 10 was prepared according to Step 5 of Example 1, except that the phenylboronic acid in Step 5 of Example 1 was replaced with (4-propylphenyl)boronic acid. The resulting compound was a white solid with an 87% yield and a melting point of 132.2-133.5°C. The compound's structural data are as follows: 1 H NMR(600MHz,DMSO-d6)δ11.32(s,1H),7.60–7.58(m,3H),7.26–7.24(m,3H),7.21-7.18(m,1H),2.87–2.84(m ,2H),2.59–2.57(m,2H),2.54–2.52(m,2H),2.21(s,6H),1.62(dt,J=15.0,7.4Hz,2H),0.92(t,J=7.3Hz,3H). 13 C NMR (151MHz, DMSO-d6) δ149.36 (d, J = 241.60Hz), 140.51, 138.22, 131.72 (d, J = 6.04Hz), 131.54 (d, J = 6.04Hz), 128.82 (2C), 126.63 (2C), 124.4 1,123.12(d,J=13.59Hz),114.46,112.23,104.87(d,J=18.12Hz),59.88,45.19(2C),36.84,24.12,22.97,13.68.HR-MS(ESI):Calcdfor[M+H] + 325.2124;Found:325.2080.

[0154] Example 11: Preparation of (Compound 11)

[0155] 1. Preparation of 4-bromo-2-fluoroaniline

[0156] 4-Bromo-2-fluoroaniline was prepared according to Step 1 of Example 1.

[0157] 2. Preparation of diazo solution

[0158] Prepare diazo solution according to step 2 of Example 1.

[0159] 3. Preparation of (4-bromo-2-fluorophenyl)hydrazine

[0160] (4-Bromo-2-fluorophenyl)hydrazine was prepared according to Step 3 of Example 1.

[0161] 4. Preparation of N,N-dimethyl-5-bromo-1H-indole-3-ethylamine

[0162] N,N-Dimethyl-5-bromo-1H-indole-3-ethylamine was prepared according to Step 4 of Example 1.

[0163] 5. Preparation of Compound 11

[0164] Compound 11 was prepared according to Step 5 of Example 1, except that the phenylboronic acid in Step 5 of Example 1 was replaced with (4-(cyanomethyl)phenyl)boronic acid. The resulting compound was a white solid with an 89% yield and a melting point of 148.0-148.7°C. The compound's structural data are as follows: 1 H NMR(600MHz,DMSO-d6)δ11.37(s,1H),7.74-7.73(m,2H),7.63(s,1H),7.42-7.41(m,2 H),7.25-7.23(m,2H),4.07(s,2H),2.88-2.85(m,2H),2.55–2.52(m,2H),2.22(s,6H). 13 C NMR (151MHz, DMSO-d6) δ149.39(d,J=243.11Hz),140.09,131.74(d,J=6.04Hz),130.78(d,J=6.04Hz),129.53,128.58(2C),127.27(2C ),124.56,123.34(d,J=13.59Hz),119.33,114.59,112.57,104.92(d,J=18.12Hz),59.85,45.19(2C),22.94,21.99.HR-MS(ESI):Calcd for[M+H]+ 322.1726;Found:322.1720.

[0165] Example 12: Preparation of (Compound 12)

[0166] 1. Preparation of 4-bromo-2-fluoroaniline

[0167] 4-Bromo-2-fluoroaniline was prepared according to Example 1, Step 1.

[0168] 2. Preparation of diazo solution

[0169] Prepare diazo solution according to step 2 of Example 1.

[0170] 3. Preparation of (4-bromo-2-fluorophenyl)hydrazine

[0171] (4-Bromo-2-fluorophenyl)hydrazine was prepared according to Step 3 of Example 1.

[0172] 4. Preparation of N,N-dimethyl-5-bromo-1H-indole-3-ethylamine

[0173] N,N-Dimethyl-5-bromo-1H-indole-3-ethylamine was prepared according to Step 4 of Example 1.

[0174] 5. Preparation of Compound 12

[0175] Compound 12 was prepared according to Step 5 of Example 1, except that 4-methylbiphenylboronic acid was used instead of phenylboronic acid in Step 5 of Example 1. The resulting compound was a white solid with a yield of 90% and a melting point of 166.1-167.5°C. The compound's structural data are as follows: 1 H NMR(600MHz,DMSO-d6)δ11.37(s,1H),7.79-7.78(m,2H),7.72-7.71(m,2H),7.67(s,1H),7.62- 7.61(m,2H),7.29–7.26(m,4H),2.89–2.87(m,2H),2.56–2.54(m,2H),2.35(s,3H),2.22(s,6H). 13C NMR(151MHz,DMSO-d6)δ149.43(d,J=243.11Hz),139.49,138.23,136.84,13 6.69,131.78(d,J=6.04Hz),130.98(d,J=6.04Hz),129.58(2C),127.21(2C) ,126.80(2C),126.31(2C),124.53,123.32(d,J=12.08Hz),114.59,112.44, 104.85(d,J=16.61Hz),59.88,45.20(2C),22.97,20.69.HR-MS(ESI):Calcd for[M+H] + 373.2088;Found:373.2080.

[0176] Example 13: Preparation of (Compound 13)

[0177] 1. Preparation of 4-bromo-2-fluoroaniline

[0178] 4-Bromo-2-fluoroaniline was prepared according to Step 1 of Example 1.

[0179] 2. Preparation of diazo solution

[0180] Prepare diazo solution according to step 2 of Example 1.

[0181] 3. Preparation of (4-bromo-2-fluorophenyl)hydrazine

[0182] (4-Bromo-2-fluorophenyl)hydrazine was prepared according to Step 3 of Example 1.

[0183] 4. Preparation of N,N-dimethyl-5-bromo-1H-indole-3-ethylamine

[0184] N,N-Dimethyl-5-bromo-1H-indole-3-ethylamine was prepared according to Step 4 of Example 1.

[0185] 5. Preparation of Compound 13

[0186] Compound 13 was prepared according to Step 5 of Example 1, except that the phenylboronic acid in Step 5 of Example 1 was replaced with (4-acetylphenyl)boronic acid. The resulting compound was a white solid with a yield of 69% and a melting point of 140.9-141.4°C. The compound's structural data are as follows: 1H NMR(600MHz,DMSO-d6)δ11.45(s,1H),8.02-8.01(m,2H),7.88-7.87(m,2H),7.75(s,1H),7.34( d,J=11.9Hz,1H),7.28(s,1H),2.89–2.87(m,2H),2.61(s,3H),2.56–2.53(m,2H),2.22(s,6H). 13 C NMR (151MHz, DMSO-d6) δ197.41, 149.44 (d, J = 243.11Hz), 145.19, 134.89, 131.78 (d, J = 6.04Hz), 130.05 (d, J = 6.04Hz), 128.86 (2C), 12 6.79(2C),124.76,123.79(d,J=13.59Hz),114.90,113.29,105.05(d,J=16.61Hz),59.83,45.20(2C),26.73,22.90.HR-MS(ESI):Calcd for[M+H] + 325.1749;Found:325.1716.

[0187] Example 14: Preparation of (Compound 14)

[0188] 1. Preparation of 4-bromo-2-fluoroaniline

[0189] 4-Bromo-2-fluoroaniline was prepared according to Example 1, Step 1.

[0190] 2. Preparation of diazo solution

[0191] Prepare diazo solution according to step 2 of Example 1.

[0192] 3. Preparation of (4-bromo-2-fluorophenyl)hydrazine

[0193] (4-Bromo-2-fluorophenyl)hydrazine was prepared according to Step 3 of Example 1.

[0194] 4. Preparation of N,N-dimethyl-5-bromo-1H-indole-3-ethylamine

[0195] N,N-Dimethyl-5-bromo-1H-indole-3-ethylamine was prepared according to Step 4 of Example 1.

[0196] 5. Preparation of Compound 14

[0197] Compound 14 was prepared according to Step 5 of Example 1, except that the phenylboronic acid in Step 5 of Example 1 was replaced with (4-heptylphenyl)boronic acid. The resulting compound was a white solid with an 85% yield and a melting point of 100.5-100.6°C. The compound's structural data are as follows: 1 H NMR(600MHz,DMSO-d6)δ11.32(s,1H),7.60–7.58(m,3H),7.25-7.24(m,3H),7.19(dd,J=12.8,1.1Hz,1H),2.87–2.8 4(m,2H),2.60(t,J=7.6Hz,2H),2.55–2.52(m,2H),2.21(s,6H),1.61–1.56(m,2H),1.29(s,6H),0.87–0.85(m,3H). 13 C NMR(151MHz,DMSO-d6)δ149.37(d,J=243.11Hz),140.74,138.16,131.72( d,J=6.04Hz),131.54(d,J=6.04Hz),128.76(2C),126.63(2C),124.41,123 .12(d,J=13.59Hz),114.44,112.22,104.87(d,J=16.61Hz),59.88,45.19 (2C),34.73,31.15,30.98,28.37,22.97,22.10,13.98.HR-MS(ESI):Calcd for[M+H] + 367.2599;Found:367.2550.

[0198] Example 15: Preparation of (Compound 15)

[0199] 1. Preparation of 4-bromo-2-fluoroaniline

[0200] 4-Bromo-2-fluoroaniline was prepared according to Step 1 of Example 1.

[0201] 2. Preparation of diazo solution

[0202] Prepare diazo solution according to step 2 of Example 1.

[0203] 3. Preparation of (4-bromo-2-fluorophenyl)hydrazine

[0204] (4-Bromo-2-fluorophenyl)hydrazine was prepared according to Step 3 of Example 1.

[0205] 4. Preparation of N,N-dimethyl-5-bromo-1H-indole-3-ethylamine

[0206] N,N-Dimethyl-5-bromo-1H-indole-3-ethylamine was prepared according to Step 4 of Example 1.

[0207] 5. Preparation of Compound 15

[0208] Compound 15 was prepared according to Step 5 of Example 1, except that the phenylboronic acid in Step 5 of Example 1 was replaced with (4-(trifluoromethyl)phenyl)boronic acid. The resulting compound was a white solid with a yield of 49% and a melting point of 182.1-183.5°C. The compound's structural data are as follows: 1 H NMR(600MHz,DMSO-d6)δ11.46(s,1H),7.95-7.93(m,2H),7.78-7.77(m,2H),7.73(s,1H),7.32(d d,J=12.7,1.2Hz,1H),7.29(d,J=2.1Hz,1H),2.89–2.87(m,2H),2.56–2.53(m,2H),2.22(s,6H). 13 C NMR (151MHz, DMSO-d6) δ149.44(d,J=243.11Hz),144.76,131.78(d,J=6.04Hz),129.72(d,J=6.04Hz),127.44(2C),126.95(d,J=31.7 1Hz),125.64,125.62,124.81,123.83,123.74,114.87,113.35,105.08(d,J=18.12Hz),59.82,45.18(2C),22.90.HR-MS(ESI):Calcd for[M+H] + 351.1551;Found:351.1484.

[0209] Example 16: Preparation of (Compound 16)

[0210] 1. Preparation of 4-bromo-2-fluoroaniline

[0211] 4-Bromo-2-fluoroaniline was prepared according to Example 1, Step 1.

[0212] 2. Preparation of diazo solution

[0213] Prepare diazo solution according to step 2 of Example 1.

[0214] 3. Preparation of (4-bromo-2-fluorophenyl)hydrazine

[0215] (4-Bromo-2-fluorophenyl)hydrazine was prepared according to Step 3 of Example 1.

[0216] 4. Preparation of N,N-dimethyl-5-bromo-1H-indole-3-ethylamine

[0217] N,N-Dimethyl-5-bromo-1H-indole-3-ethylamine was prepared according to Step 4 of Example 1.

[0218] 5. Preparation of Compound 16

[0219] Compound 16 was prepared according to Step 5 of Example 1, except that the phenylboronic acid in Step 5 of Example 1 was replaced with m-tolylboronic acid. The resulting compound was a white solid with a yield of 78% and a melting point of 123.8-124.1°C. The compound's structural data are as follows: 1 H NMR (600MHz, DMSO-d6) δ11.33(s,1H),7.60(s,1H),7.52(s,1H),7.48(d,J=7.8Hz,1H),7.32(t,J=7.6Hz,1H),7.25(d,J=1.8 Hz,1H),7.21(dd,J=13.2,1.2Hz,1H),7.13(d,J=7.8Hz,1H),2.88–2.85(m,2H),2.55–2.53(m,2H),2.39(s,3H),2.22(s,6H). 13 C NMR(151MHz, DMSO-d6)δ149.34(d,J=243.11Hz),140.73,137.90,131.72,131.65(d,J=6.04Hz),128.70,127.46,127.26,124.4 3,123.93,123.22(d,J=13.59Hz),114.51,112.46,104.99(d,J=18.12Hz),59.84,45.20(2C),22.96,21.16.HR-MS(ESI):Calcd for[M+H] + 297.1830;Found:297.1767.

[0220] Example 17: Preparation of (Compound 17)

[0221] 1. Preparation of 4-bromo-2-fluoroaniline

[0222] 4-Bromo-2-fluoroaniline was prepared according to Example 1, Step 1.

[0223] 2. Preparation of diazo solution

[0224] Prepare diazo solution according to step 2 of Example 1.

[0225] 3. Preparation of (4-bromo-2-fluorophenyl)hydrazine

[0226] (4-Bromo-2-fluorophenyl)hydrazine was prepared according to Step 3 of Example 1.

[0227] 4. Preparation of N,N-dimethyl-5-bromo-1H-indole-3-ethylamine

[0228] N,N-Dimethyl-5-bromo-1H-indole-3-ethylamine was prepared according to Step 4 of Example 1.

[0229] 5. Preparation of Compound 17

[0230] Compound 17 was prepared according to Step 5 of Example 1, except that the phenylboronic acid in Step 5 of Example 1 was replaced with o-tolylboronic acid. The resulting compound was a white solid with an 85% yield and a melting point of 114.6-114.9°C. The compound's structural data are as follows: 1 H NMR (600MHz, DMSO-d6) δ11.34 (s, 1H), 7.30-7.24 (m, 6H), 6.88 (dd, J = 12.0Hz ,1.2Hz,1H),2.83–2.81(m,2H),2.53-2.51(m,2H),2.26(s,3H),2.19(s,6H). 13 CNMR(151MHz,DMSO-d6)δ148.55(d,J=243.11Hz),141.74,134.95,132.08(d,J=6.04Hz),131.15(d,J=6.04Hz),130.25,129.98,126.8 7,125.81,124.33,122.80(d,J=13.59Hz),114.84,114.22,107.17(d,J=16.61Hz),59.92,45.16(2C),22.96,20.37.HR-MS(ESI):Calcd for[M+H] + 297.1816;Found:297.1767. Specific embodiment three

[0232] The use of the compound prepared in the above embodiment 1 or embodiment 2 in the preparation of a drug. The drug is a potential 5-HT 1B Agonists of 5-HT receptors that can effectively 1B It binds to the cytochrome P64 receptor, thereby inhibiting the activity of adenylate cyclase, which may prevent and or treat migraine.

[0233] It should be noted that the above-mentioned drugs of the present invention can be introduced into the body by injection, spraying, nasal drops, eye drops, penetration, absorption, physical or chemical mediation methods, such as intramuscular, intradermal, subcutaneous, intravenous, and mucosal tissues; they can also be mixed with or encapsulated by other substances and introduced into the body. When necessary, one or more pharmaceutically acceptable carriers can also be added to the above-mentioned drugs. The carriers include conventional diluents, excipients, fillers, adhesives, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field. In addition, the drugs of the present invention can be prepared into various forms such as injections, tablets, powders, granules, capsules, oral liquids, ointments, creams, etc. The drugs in the above-mentioned various dosage forms can all be prepared according to conventional methods in the pharmaceutical field.

[0234] Example 1

[0235] In vitro functional activity test

[0236] Recombinant human 5HT 1B cAMP agonist function assay was performed on R stable cell line (CHO-K1). The cells were cultured in culture medium (90% F12K + 10% FBS + 800 μg / mL G418) at 37 ° C and 5% CO2. The positive compound 5-hydroxytryptamine (5-HT) was diluted 3 times starting from 1uM. The positive compound sumatriptan and all synthetic compounds were diluted 5 times starting from a concentration of 200uM. Then, 50nL of compound was transferred by Echo machine. Cells were collected with buffer (1×HBSS containing 5mM HEPES + 0.5mM IBMX + 0.1% BSA) and plated at an appropriate density. The cells were centrifuged at 600rpm for 3 minutes and then incubated with the compound at room temperature for 60 minutes. After that, 5uL 4X Eu-cAMP tracer solution and 5uL 4XULight TM Anti-cAMP solution was added to the cells, centrifuged at 600 rpm for 3 minutes, and incubated for 60 minutes. cAMP signal was detected using Envision. GraphPad Prism (version 6.0) was used for data analysis. The experimental results are shown in Table 1.

[0237]

[0238] Table 1 In vitro functional activity test results of compounds 1-17

[0239]

[0240]

[0241]

[0242] Note: EC50 represents half-maximal effect concentration.

[0243] Table 1 shows the cAMP method 5-HT of 7-fluoro-5-substituted tryptamine compounds 1B The results of R agonist activity screening show that when the R substituent is a phenyl group, the compound has a strong effect on 5-HT 1B The agonist activity of R was significantly improved compared with that of biphenyls, among which compounds 6 and 11 had the highest agonist activity (e.g. Figure 1 As shown), 5-HT 1B EC of R 50 The activity of the compounds was 10.77nM and 8.57nM, respectively, which were 3-fold and 4-fold higher than the positive control, sumatriptan succinate. Adding methyl groups at different positions of the phenyl group in the R group did not significantly change the activity of the compounds, with activity values around 100nM.

[0244] Example 2

[0245] With 5-HT 1B Receptor binding affinity

[0246] 5-HT obtained from commercial channels 1BRadioligand binding assay was performed on cell membranes. The specific operation was as follows: the test compound was diluted 5-fold in DMSO with 8 concentration gradients, starting at a concentration of 20uM. The positive reference compound 5-HT was diluted 4-fold in DMSO with 8 concentration gradients, starting at a concentration of 10uM. The positive compounds sumatriptan succinate and rizatriptan benzoate were diluted 5-fold in DMSO with 8 concentration gradients, starting at a concentration of 20uM. Transfer 1uL of the diluted positive compound and the test compound to the designated positions in the experimental plate, transfer 1uL of the nonspecific binding compound to the experimental plate as the nonspecific binding well (LC), and transfer 1uL of DMSO to the experimental plate as the total binding well (HC). Add 100uL of the prepared cell membrane and isotope to the experimental plate, seal the plate, and incubate the reaction plate on a shaker at 300rpm at room temperature for 2 hours. Soak each well of a GF / C plate in 50 μL of 0.3% PEI for at least half an hour. After incubation, rinse the plate once with plate wash buffer using Harvest. Then, collect the cell membranes from the 96-well plate onto the GF / C plate using Harvest. Wash the plate four times with plate wash buffer, using approximately 250 μL each time. Place the plate in a 50°C oven for 1 hour, seal the bottom of the plate with sealing film, add 50 μL of Microscint-20 scintillation fluid to each well, and seal the plate with transparent sealing film. Read the plate using a MicroBeta2 reader, and analyze the data using GraphPad Prism 5.0. The results are shown in Table 2.

[0247]

[0248] Table 2 Binding affinity activity results of compounds 1-17

[0249]

[0250]

[0251]

[0252] Table 2 shows the relationship between 7-fluoro-5-substituted tryptamine compounds and 5-HT 1B The results show that when the R substituent is a straight-chain alkane, the binding is weaker than that of phenyl, and the biphenyl substituent is weaker than that of phenyl. In summary, the R substituent of the compound is phenyl and has a strong affinity with 5-HT. 1BThe binding of most compounds to 5-HT receptor was the best, and the binding of most compounds was stronger than that of the positive control compounds sumatriptan succinate and rizatriptan benzoate. 1B The binding activity of R Figure 2 As shown, the binding activity of compound 11 (K i =16.56 nM) than the positive compound serotonin (K i =21.00) is better, the activity of compound 6 (K i =36.95nM) than the positive controls sumatriptan succinate and rizatriptan benzoate. 1B Sumatriptan, which targets 5-HT receptors, has anti-migraine, vasoconstriction and analgesic effects. The compound of the present invention targets 5-HT 1B receptors and binds to active K i and half-maximal effect concentration (EC) 50 It is superior to the marketed drug sumatriptan and has anti-migraine, vasoconstrictor and analgesic effects.

[0253] The above description is not intended to limit the present invention, and the present invention is not limited to the above examples. Any changes, modifications, additions or substitutions made by persons of ordinary skill in the art within the spirit and scope of the present invention shall also fall within the scope of protection of the present invention.

Claims

1. A 7-fluoro-5-substituted tryptamine compound, characterized in that The compound is at least one of the following structural formulas or a pharmaceutically acceptable salt thereof: The pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt. The inorganic acid salt is a salt formed by any one of hydrochloric acid, sulfuric acid and phosphoric acid; the organic acid salt is a salt formed by any one of acetic acid, trifluoroacetic acid, malonic acid, succinic acid, citric acid and p-toluenesulfonic acid.

2. A 7-fluoro-5-substituted tryptamine compound according to claim 1, characterized in that The compound is at least one of the following structural formulas 3. A method for preparing the 7-fluoro-5-substituted tryptamine compound according to claim 1, characterized in that The following steps are involved: (1) reacting the compound represented by formula II with iron and ammonium chloride to obtain the compound represented by formula III; (2) reacting the compound represented by formula III with sodium nitrite to obtain the compound represented by formula IV; (3) reacting the compound represented by formula IV with stannous chloride to obtain the compound represented by formula V; (4) reacting the compound represented by Formula V with the compound represented by Formula VI to obtain the compound represented by Formula VII; (5) reacting the compound represented by formula VII with the compound represented by formula VIII to obtain the compound represented by formula I, wherein R is phenyl, 4-methylphenyl, biphenyl, 4-chlorophenyl, 4-hydroxyphenyl, propyl, 4-methoxyphenyl, 4-vinylphenyl, 4-propylphenyl, p-(2-cyanoethyl)phenyl, 4-methyl-1,1′-biphenyl, 4-hexylphenyl, 4-trifluoromethylphenyl, 3-methylphenyl, or 2-methylphenyl.

4. The method for preparing a 7-fluoro-5-substituted tryptamine compound according to claim 3, characterized in that Step (1) is specifically as follows: using iron as a reducing agent, the compound represented by formula II is reacted with iron and ammonium chloride in anhydrous ethanol at a molar ratio of 1:5:3 at 40-60° C. for 2 hours to obtain the compound represented by formula III.

5. The method for preparing a 7-fluoro-5-substituted tryptamine compound according to claim 3, characterized in that Step (2) is specifically as follows: reacting the compound represented by formula III with sodium nitrite at 0° C. for half an hour to obtain a solution of the compound represented by formula IV.

6. The method for preparing a 7-fluoro-5-substituted tryptamine compound according to claim 3, characterized in that Step (3) is specifically as follows: reacting the compound represented by formula IV with stannous chloride at 0° C. for 2 hours to obtain the compound represented by formula V.

7. The method for preparing a 7-fluoro-5-substituted tryptamine compound according to claim 3, characterized in that Step (4) is specifically as follows: reacting the compound represented by formula V with the compound represented by formula VI in a 4% sulfuric acid solution at 60-100° C. for 2-12 hours to obtain the compound represented by formula VII.

8. The method for preparing a 7-fluoro-5-substituted tryptamine compound according to claim 3, characterized in that Step (5) is specifically as follows: reacting the compound represented by Formula VII and the compound represented by Formula VIII with [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride and potassium phosphate in a 1,4-dioxane solution at 80-100°C for 6-12 hours to obtain the compound represented by Formula I.

9. Use of the 7-fluoro-5-substituted tryptamine compound according to claim 1 or 2 in the preparation of a drug for treating migraine.

10. The use according to claim 9, characterized in that: The drug is 5-HT 1B Receptor agonists.

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