CN113173918B

CN113173918B - N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative and preparation method and application thereof

Info

Publication number: CN113173918B
Application number: CN202110538108.6A
Authority: CN
Inventors: 王绍杰; 段雨琳; 杨玉威
Original assignee: Shenyang Pharmaceutical University
Current assignee: Shenyang Pharmaceutical University
Priority date: 2021-05-18
Filing date: 2021-05-18
Publication date: 2022-04-05
Anticipated expiration: 2041-05-18
Also published as: CN113173918A

Abstract

The invention discloses an N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative, a preparation method and application thereof, belongs to the technical field of medicines, and discloses an N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative which is innovatively applied to the design of a non-purine xanthine oxidase inhibitor in a form of amide serving as a connecting fragment and synthesized. The ultraviolet spectrophotometry is adopted to carry out in vitro xanthine oxidase inhibition activity test on the designed compound, and the prepared compound shows obvious xanthine oxidase inhibition activity. In an acute hyperuricemia rat model test, the compound can obviously reduce the serum uric acid level, and has good deep research value as a novel xanthine oxidase inhibitor.

Description

N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative and preparation method and application thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to an N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative, and a preparation method and application thereof.

Background

Hyperuricemia is a metabolic disease in which the concentration of uric acid in serum is too high due to excessive production or decreased excretion of uric acid, and hyperuricemia was defined as a blood uric acid concentration higher than 6.6mg/dL by the European League Against Rheumatism rheummation (EULAR) in 2006. Although hyperuricemia is not a fatal disease, it is associated with a series of chronic diseases such as hypertension, insulin resistance, chronic renal dysfunction, cardiovascular diseases, etc., and when the concentration of uric acid is higher than 6.6mg/dL, it may be crystallized and deposited at a site where the body temperature is lower than 37 ℃ to cause gout. Clinically, gout is characterized by an acute attack of inflammation of the joints, which if left untreated, recurs in multiple joints, which may progress to joint destruction, which will have a serious impact on quality of life. Epidemiological studies have shown that the incidence and prevalence of gout are increasing year by year. Xanthine oxidase (xanteneoxidase, XO), which is a key rate-limiting enzyme in the purine metabolic pathway to uric acid, has become an important target for treating hyperuricemia and gout.

Disclosure of Invention

The invention aims to provide N-indole-1, 6-dihydropyrimidine-4-carboxamide derivatives with xanthine oxidase inhibitory activity, a preparation method thereof and application thereof in preparing anti-gout medicaments.

N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative shown as general formula I or pharmaceutically acceptable salt, isomer, polymorph and pharmaceutically acceptable solvate thereof.

Wherein R is¹H, C1-C6 alkyl, C2-C6 alkenyl, substituted or unsubstituted benzyl, the substituent is halogen or C1-C6 alkyl; r²Is H, methyl or hydroxy.

Specifically, the invention provides an N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative which is any one of the following compounds D1-5 to Y1-2:

d1-5: n- (3-cyano-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D2-5: n- (3-cyano-1-methyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D3-5: n- (3-cyano-1-isopropyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D4-5: n- (3-cyano-1-isobutyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D5-5: n- (3-cyano-1-isopentyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D6-5: n- (3-cyano-1-allyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D7-5: n- [ 3-cyano-1- (3-methylbut-2-en-1-yl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D8-5: n- [ 3-cyano-1- (prop-2-yn-1-yl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D9-5: n- [ 3-cyano-1- (cyclopropylmethyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D10-5: n- (3-cyano-1-cyclopentyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D11-5: n- [ 3-cyano-1- (cyclohexylmethyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D12-5: n- (3-cyano-1-benzyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D13-5: n- [ 3-cyano-1- (4-methylbenzyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D14-5: n- [ 3-cyano-1- (4-methoxybenzyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D15-5: n- [ 3-cyano-1- (4-tert-butylbenzyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D16-5: n- [ 3-cyano-1- (4-fluorobenzyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D17-5: n- [ 3-cyano-1- (4-chlorobenzyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D18-5: n- [ 3-cyano-1- (4-bromobenzyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D19-5: n- [ 3-cyano-1- (3-fluorobenzyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D20-5: n- [ 3-cyano-1- (3-chlorobenzyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D21-5: n- [ 3-cyano-1- (2-fluorobenzyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D22-5: n- [ 3-cyano-1- (2-chlorobenzyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

D23-5: n- [ 3-cyano-1- (2-hydroxy-2-methylpropyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

L1-5: n- (3-cyano-1-isobutyl-1H-indol-6-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

L2-5: n- (3-cyano-1-isopropyl-1H-indol-6-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

L3-5: n- (3-cyano-1-cyclopentyl-1H-indol-6-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

L4-5: n- [ 3-cyano-1- (cyclopropylmethyl) -1H-indol-6-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

L5-5: n- [ 3-cyano-1- (3-methylbut-2-en-1-yl) -1H-indol-6-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

L6-5: n- (3-cyano-1-allyl-1H-indol-6-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

Y1-1: n- (3-cyano-1-cyclopentyl-1H-indol-5-yl) -2-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide

Y1-2: n- (3-cyano-1-cyclopentyl-1H-indol-5-yl) -2, 6-dioxo-1, 2,3, 6-tetrahydropyrimidine-4-carboxamide

The invention also provides an intermediate for preparing the N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative or the pharmaceutically acceptable salt thereof, wherein the structure of the intermediate is shown as the general formula II or III:

wherein R is¹H, C1-C6 alkyl, C2-C6 alkenyl and substituted or unsubstituted benzyl, wherein the substituent is halogen or C1-C6 alkyl.

Specifically, the intermediate is any one of compounds D1-3 to L6-4 shown below;

such isomers include, but are not limited to: stereoisomers, geometric isomers and tautomers.

The pharmaceutically acceptable salts refer to organic salts and inorganic salts of the compounds of the invention, including: hydrochloride, sulfate, sodium, potassium and ammonium salts.

The solvate refers to an association formed by one or more solvent molecules and the compound provided by the invention. Solvents that form solvates include, but are not limited to: water, methanol, ethanol, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dichloromethane, toluene and DMF.

The invention also provides a preparation method of the N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative, which comprises the following steps:

5/6-nitro-1H-indole (D-0 or L-0) is taken as a starting material, Vilsmeier-Haack reaction and cyanidation reaction are sequentially carried out to obtain a common intermediate 5/6-nitro-1H-indole-3-carbonitrile (D-2 or L-2), 5/6-nitro-1H-indole-3-carbonitrile reacts with different halogenated hydrocarbons to obtain a corresponding intermediate 1-alkyl-5/6-nitro-1H-indole-3-carbonitrile (Dx-3 or Lx-3), and then the 1-alkyl-5/6-nitro-1H-indole-3-carbonitrile is reduced into a corresponding intermediate 1-alkyl-5/6-amino-1H-indole ion-carboxylic acid by zinc powder 3-formonitrile (Dx-4 or Lx-4) hydrochloride, finally, 1-alkyl-5/6-amino-1H-indole-3-formonitrile hydrochloride and 6-oxo-1, 6-dihydropyrimidine-4-carboxylic acid are condensed with amide to obtain the compound shown in the general formula I;

the invention provides a pharmaceutical composition, which comprises one or more of the N-indole-1, 6-dihydropyrimidine-4-carboxamide derivatives or pharmaceutically acceptable salts, isomers, polymorphs, pharmaceutically acceptable solvates thereof; also comprises one or the combination of pharmaceutically acceptable auxiliary materials, carriers and diluents. The routes of administration of the pharmaceutical composition include: oral, nasal, transdermal, pulmonary and parenteral administration, preferably by the oral route. In particular, so long as it is effective in delivering the active agent to the desired site of activity, for example, by rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or ointment routes. The dosage form of the pharmaceutical composition comprises: tablets, capsules, lozenges, syrups, emulsions, injections, aerosols and dragees. The weight percentage of the N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative or the pharmaceutically acceptable salt, isomer, polymorph and pharmaceutically acceptable solvate thereof in the pharmaceutical composition for inhibiting the xanthine oxidase activity is 0.5-20%, preferably 0.5-10%.

Pharmaceutical compositions containing the compounds of the present invention may be prepared by conventional methods, for example as described in Remington, the Science and Practice of Pharmacy,19th ed., 1995. In particular, the composition may be in a conventional form such as a capsule, tablet, powder, solution, suspension, syrup, aerosol or topical form. They may be formulated in solutions or suspensions for injection using a suitable solid or liquid carrier in a suitable sterile medium.

The carrier is any one or more of water, salt solution, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, coconut oil, gelatin, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ether of cellulose, silicic acid, fatty acid amine, fatty acid monoglyceride and diglyceride, quaternary tetraol fatty acid ester, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone. The formulation may also include wetting agents, emulsifying agents, suspending agents, preserving agents, sweetening agents or flavoring agents. The formulations of the present invention may be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient by methods known in the art.

The pharmaceutical compositions may be sterile and may, if desired, be mixed with adjuvants, emulsifiers, buffers and/or colorants and the like, provided that they do not react with the active compound.

For intranasal administration, the formulations may contain an aerosol for administration dissolved or suspended in a liquid carrier, particularly an aqueous carrier. The vehicle may contain additives including solubilizing agents such as propylene glycol, surfactants, absorption enhancers such as lecithin (phosphocholine) or cyclodextrin, preservatives such as parabens.

For parenteral administration, particularly suitable are injection solutions or suspensions, preferably aqueous solutions of the active compound in a polyhydroxylated castor oil.

Tablets, dragees or capsules having talc and/or carbohydrate carriers or binders are particularly suitable for oral administration. Carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. When a sugar-added carrier can be used, a syrup or an alcoholism agent can be used.

The invention also provides an application of the N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative or the pharmaceutically acceptable salt thereof or the pharmaceutical composition, and the N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative or the pharmaceutically acceptable salt thereof can be used for treating and/or preventing hyperuricemia and gout drugs.

Amide bonds play a key role in the composition of many biologically active molecules, including polypeptides, proteins, and a variety of chemical probes, as well as clinically recognized synthetic and natural products. The reasonable introduction of amido bond can enhance the activity and selectivity of drug molecules, improve the pharmacokinetic property of the compound and improve the drug effect of the compound. The invention uses amido bond as a connecting fragment in the molecular design of non-purine with xanthine oxidase inhibition effect to prepare the N- (3-cyano-1H-indole-5/6-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide compound.

The molecular simulation research shows that the pyrimidine ring of the N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative provided by the invention forms pi-pi stacking action with amino acids Phe914 and Phe1009, the carbonyl at the 6-position of pyrimidine forms hydrogen bond action with Arg880 and Thr1010, the N at the 1-position of pyrimidine forms hydrogen bond action with Glu802, the amide carbonyl forms hydrogen bond action with Glu802, and the cyano at the 3-position of indole forms hydrogen bond action with subcloth Asn768 and Lys 771. In addition, the hydrophobic group at position 1 of the indole of the derivative forms a hydrophobic interaction with the amino acid at the entrance of the active site. The above results explain the reason why the derivative provided by the present invention has XO inhibitory activity.

The invention has the beneficial effects that:

the invention innovatively adopts amide as a connecting fragment to be applied to the design of a non-purine xanthine oxidase inhibitor, and synthesizes the N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative. The ultraviolet spectrophotometry is adopted to carry out in-vitro xanthine oxidase inhibition activity test on the designed compound, and the result shows that most target compounds show obvious xanthine oxidase inhibition activity. In an acute hyperuricemia rat model test, the compound D10-5 can obviously reduce the serum uric acid level, and has good deep research value as a novel xanthine oxidase inhibitor.

Drawings

FIG. 1 shows the results of uric acid lowering activity of the compound D10-5 of example 2 in a rat model of acute hyperuricemia.

Detailed Description

The invention will now be further illustrated with reference to the following examples, but is not limited thereto.

Example 1: preparation of N- (3-cyano-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D1-5)

Preparation of 5-nitro-1H-indole-3-carbaldehyde (D-1): adding 5-nitro-1H-indole D-0(2g,12.3mmol) and DMF (40mL) into a reaction bottle, stirring at 0 ℃ for 30min, then dropwise adding phosphorus oxychloride (3mL), controlling the temperature to be 0 ℃, completing dropwise addition within about 10min, then stirring at room temperature for 2H, monitoring the reaction by TLC, after the reaction is finished, adding the reaction solution into 300mL of ice water, adjusting the pH to be 8-9 by using 1N NaOH aqueous solution, separating out yellow solid, stirring at room temperature for 30min, carrying out suction filtration, washing a filter cake with water, and drying. 1.8g of D-1 was obtained as a yellow solid in yield: 76.9 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ12.63(s,1H),10.04(s,1H),8.94(s,1H),8.57(s,1H),8.15(d,J＝8.8Hz,1H),7.72(d,J＝9.0Hz,1H).ESI-MS:m/z 189.08[M-H]^-.

Preparation of 5-nitro-1H-indole-3-carbonitrile (D-2):adding D-1(1.5g,7.9mmol), hydroxylamine hydrochloride (1.1g,16mmol), sodium formate (2.2g,32mmol), formic acid (20mL) and NMP (2mL) into a reaction bottle, carrying out reflux reaction at 105 ℃ for 3h, gradually dissolving the solid in the reaction process, monitoring the reaction by TLC, cooling to room temperature after the reaction is finished, adding equivalent water into the reaction liquid, separating out a tan solid, stirring at room temperature for 30min, carrying out suction filtration, washing the filter cake with water, and drying. 1.1g of D-2 was obtained as a yellow solid in yield: 74.8 percent.¹H NMR(400MHz,DMSO-d₆)δ12.82(s,1H),8.53(s,1H),8.50(d,J＝2.2Hz,1H),8.15(dd,J＝9.0,2.3Hz,1H),7.76(d,J＝9.0Hz,1H).ESI-MS:m/z 186.09[M-H]^-.

Preparation of 5-amino-1H-indole-3-carbonitrile (D1-4) hydrochloride salt: adding D-2(1.9g,10mmol), zinc powder (19.8g,300mmol), ammonium chloride (10.8g,200mmol) and absolute ethyl alcohol (40mL) into a reaction bottle, stirring at 50 ℃ for 1h, monitoring by TLC after the reaction is completed, cooling the reaction solution to room temperature, carrying out suction filtration, washing a filter cake with water and ethyl acetate, extracting the filtrate with ethyl acetate, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate for 2h, carrying out suction filtration to remove inorganic salts, distilling off ethyl acetate under reduced pressure, adding 1N HCl/EA 20mL, stirring at room temperature for 1h, precipitating a white solid, carrying out suction filtration, washing the filter cake with ethyl acetate to obtain 1.5g of a white solid D1-4 hydrochloride, wherein the yield is as follows: 77.3 percent. M.p 252.1.1-253.9 ℃,¹H NMR(400MHz,DMSO-d₆)δ12.70(d,J＝2.9Hz,1H),10.55(s,3H),8.39(d,J＝2.9Hz,1H),7.73-7.70(m,2H),7.35(dd,J＝8.6,2.1Hz,1H).MS:m/z 158.0[M+H]⁺.

preparation of N- (3-cyano-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D1-5): adding D1-4 hydrochloride (0.5g,2.6mmol), 6-oxo-1, 6-dihydropyrimidine-4-carboxylic acid (0.35g,2.5mmol), HATU (1.24g,3.25mmol), N-diisopropylethylamine (2mL) and DMF (20mL) into a reaction flask, stirring at room temperature for 10h, monitoring the completion of the reaction by TLC, adding a proper amount of water into the reaction flask, adding 1N HCl to adjust the pH to 3-4, precipitating a large amount of yellow solid, continuing stirring for 1h, carrying out suction filtration, washing a filter cake with water, drying, carrying out thermal pulping with tetrahydrofuran for 2h, carrying out suction filtration, carrying out thermal pulping with acetone for 1h, carrying out suction filtration, drying to obtain 0.28g of yellow solid D1-5, wherein the yield is as follows: 41 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ12.95(s,1H),12.20(s,1H),10.48(s,1H),8.38(s,1H),8.33(d,J＝2.0Hz,1H),8.24(s,1H),7.68(dd,J＝8.9,2.1Hz,1H),7.54(d,J＝8.8Hz,1H),6.98(s,1H).13C NMR(101MHz,DMSO-d6)δ162.16,161.30,155.04,150.77,135.45,132.96,132.77,127.30,118.21,116.78,114.59,113.47,110.21,84.90.ESI-HRMS:Calcd.for C₁₄H₉N₅O₂[M–H]^-278.0683,found:278.0692.

Example 2: preparation of N- (3-cyano-1-methyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D2-5)

5-Nitro-1H-indole-3-carbonitrile (D-2) was obtained by the same procedure as in example 1.

Preparation of 1-methyl-5-nitro-1H-indole-3-carbonitrile (D2-3): adding D-2(1.9g,10mmol), methyl iodide (1.5g,10.6mmol), potassium carbonate (2.1g,15mmol), potassium iodide (0.12g,0.7mmol) and DMF (30mL) into a reaction bottle, reacting at 60 ℃ for 5h, monitoring by TLC, cooling to room temperature after the reaction is finished, adding an equal amount of water into the reaction solution, precipitating a yellow solid, stirring at room temperature for 1h, filtering, washing the filter cake with water, and drying. 1.8g of D-2 was obtained as a yellow solid in yield: 90 percent. M.p 167.0-168.4 ℃ of the total weight of the mixture,¹H NMR(400MHz,DMSO-d₆)δ8.48(s,1H),8.39(d,J＝2.4Hz,1H),8.15(dd,J＝9.1,2.3Hz,1H),7.82(d,J＝9.1Hz,1H),3.95(s,3H).ESI-MS:m/z 202.0[M+H]⁺.

preparation of 1-methyl-5-amino-1H-indole-3-carbonitrile (D2-4) hydrochloride: adding D2-3(1.9g,11mmol), zinc powder (19.8g,300mmol), ammonium chloride (10.8g,200mmol) and absolute ethyl alcohol (40mL) into a reaction bottle, stirring for 1h at 50 ℃, after TLC monitoring reaction is completed, cooling the reaction solution to room temperature, carrying out suction filtration, washing a filter cake with water and ethyl acetate, extracting the filtrate with ethyl acetate, washing with water and saturated salt water, drying for 2h by using anhydrous sodium sulfate, carrying out suction filtration to remove inorganic salts, distilling off ethyl acetate under reduced pressure, adding 1N HCl/EA 20mL into the mixture, stirring for 1h at room temperature, separating out a white solid, carrying out suction filtration, washing the filter cake with ethyl acetate, obtaining 1.6g of white solid D2-4 hydrochloride, wherein the yield is as follows: 77.3 percent. M.p 259.1-260.0 ℃ of the total weight of the mixture,¹H NMR(400MHz,DMSO-d₆)δ10.62(s,3H),8.37(s,1H),7.76(d,J＝8.8Hz,1H),7.71(d,J＝1.9Hz,1H),7.39(dd,J＝8.8,2.0Hz,1H),3.90(s,3H).MS:m/z 172.0[M+H]⁺.

preparation of N- (3-cyano-1-methyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D2-5): adding D2-4 hydrochloride (0.5g,2.6mmol), 6-oxo-1, 6-dihydropyrimidine-4-carboxylic acid (0.35g,2.5mmol), HATU (1.24g,3.25mmol), N-diisopropylethylamine (2mL) and DMF (20mL) into a reaction flask, stirring at room temperature for 10h, monitoring the completion of the reaction by TLC, adding a proper amount of water into the reaction flask, adding 1N HCl to adjust the pH to 3-4, precipitating a large amount of yellow solid, continuing stirring for 1h, carrying out suction filtration, washing a filter cake with water, drying, carrying out thermal pulping with tetrahydrofuran for 2h, carrying out suction filtration, carrying out thermal pulping with acetone for 1h, carrying out suction filtration, drying to obtain 0.25g of yellow solid D2-5, wherein the yield is as follows: 40.8 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ13.02(s,1H),10.51(s,1H),8.37(s,1H),8.33(d,J＝1.9Hz,1H),8.23(s,1H),7.74(dd,J＝8.9,2.0Hz,1H),7.62(d,J＝8.9Hz,1H),6.97(s,1H),3.87(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ162.26,161.40,154.98,150.88,138.55,133.47,133.31,127.60,118.12,116.46,114.56,112.10,110.28,83.67,33.92.ESI-HRMS:Calcd.for C₁₅H₁₁N₅O₂[M–H]^-292.0840,found:292.0814.

Example 3: preparation of N- (3-cyano-1-isopropyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D3-5)

Preparation of 1-isopropyl-5-nitro-1H-indole-3-carbonitrile (D3-3): d-2(1.9g,10mmol), bromoisopropane (1.8g,10.5mmol), potassium carbonate (2.1g,15mmol), potassium iodide (0.12g,0.7mmol) and DMF (30mL) are added into a reaction bottle, reacted for 5h at 60 ℃, monitored by TLC, cooled to room temperature after the reaction is finished, equal amount of water is added into the reaction liquid, yellow solid is precipitated, stirred for 1h at room temperature, filtered, the filter cake is washed by water and dried. 1.9g of yellow solid D3-3 are obtained, yield: 82.6 percent. M.p 153.5.5 to 155.1 ℃,¹H NMR(400MHz,DMSO-d₆)δ8.77(s,1H),8.47(d,J＝2.2Hz,1H),8.18(dd,J＝9.2,2.3Hz,1H),7.99(d,J＝9.2Hz,1H),5.02-4.95(m,1H),1.53(d,J＝6.7Hz,6H).ESI-MS:m/z 230.1[M+H]⁺.

preparation of 1-isopropyl-5-amino-1H-indole-3-carbonitrile (D3-4) hydrochloride: adding D2-3(2.0g,10mmol), zinc powder (19.8g,300mmol), ammonium chloride (10.8g,200mmol) and absolute ethyl alcohol (40mL) into a reaction bottle, stirring for 1h at 50 ℃, after TLC monitoring reaction is completed, cooling the reaction solution to room temperature, carrying out suction filtration, washing a filter cake with water and ethyl acetate, extracting the filtrate with ethyl acetate, washing with water and saturated salt water, drying for 2h by using anhydrous sodium sulfate, carrying out suction filtration to remove inorganic salts, distilling off ethyl acetate under reduced pressure, adding 1N HCl/EA 20mL into the mixture, stirring for 1h at room temperature, separating out a white solid, carrying out suction filtration, washing the filter cake with ethyl acetate, obtaining 1.8g of white solid D3-4 hydrochloride, wherein the yield is as follows: 76.9 percent. M.p 252.1.1-253.3 ℃,¹H NMR(400MHz,DMSO-d₆)δ10.58(s,1H),8.59(s,1H),7.88(d,J＝8.8Hz,1H),7.71(d,J＝3.0Hz,1H),7.37(dd,J＝9.0,2.0Hz,1H),4.90(hept,J＝6.7Hz,1H),1.50(d,J＝6.6Hz,6H).MS:m/z 200.0[M+H]⁺.

preparation of N- (3-cyano-1-isopropyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D3-5): adding D3-4 hydrochloride (0.6g,2.6mmol), 6-oxo-1, 6-dihydropyrimidine-4-carboxylic acid (0.35g,2.5mmol), HATU (1.24g,3.25mmol), N-diisopropylethylamine (2mL) and DMF (20mL) into a reaction flask, stirring at room temperature for 10h, monitoring the completion of the reaction by TLC, adding a proper amount of water into the reaction flask, adding 1N HCl to adjust the pH to 3-4, precipitating a large amount of yellow solid, continuing stirring for 1h, carrying out suction filtration, washing a filter cake with water, drying, carrying out thermal pulping with tetrahydrofuran for 2h, carrying out suction filtration, carrying out thermal pulping with acetone for 1h, carrying out suction filtration, drying to obtain 0.30g of yellow solid D3-5, wherein the yield is as follows: 37.2 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ13.00(s,1H),10.53(s,1H),8.43(s,1H),8.38(s,1H),7.75-7.70(m,2H),6.99(s,1H),4.84(hept,J＝6.6Hz,1H),1.50(d,J＝6.7Hz,6H).¹³C NMR(101MHz,DMSO-d₆)δ162.07,161.33,155.00,150.73,134.62,133.25,132.30,127.74,118.06,116.56,114.66,112.22,110.46,84.35,48.64,22.67.ESI-HRMS:Calcd.for C₁₇H₁₅N₅O₂[M–H]^-320.1153,found:320.1145.

Example 4: preparation of N- (3-cyano-1H-indol-6-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (L1-5)

Preparation of 6-nitro-1H-indole-3-carbaldehyde (L-1): adding 6-nitro-1H-indole (L-0) (2g,12.3mmol) and DMF (40mL) into a reaction bottle, stirring at 0 ℃ for 30min, then dropwise adding phosphorus oxychloride (3mL), controlling the temperature to be 0 ℃, completing dropwise addition within about 10min, then stirring at room temperature for 2H, monitoring the reaction by TLC, after the reaction is finished, adding the reaction solution into 300mL of ice water, adjusting the pH to be 8-9 by using 1N NaOH aqueous solution, separating out yellow solid, stirring at room temperature for 30min, carrying out suction filtration, washing a filter cake with water, and drying. 1.9g of L-1 was obtained as a yellow solid in yield: 78.8 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ12.63(s,1H),10.04(s,1H),8.94(s,1H),8.57(s,1H),8.15(d,J＝8.8Hz,1H),7.72(d,J＝9.0Hz,1H).ESI-MS:m/z189.08[M-H]^-.

Preparation of 6-nitro-1H-indole-3-carbonitrile (L-2): adding L-1(1.5g,7.9mmol), hydroxylamine hydrochloride (1.1g,16mmol), sodium formate (2.2g,32mmol), formic acid (20mL) and NMP (2mL) into a reaction bottle, carrying out reflux reaction at 105 ℃ for 3h, gradually dissolving the solid in the reaction process, monitoring the reaction by TLC, cooling to room temperature after the reaction is finished, adding equivalent water into the reaction liquid, separating out a tan solid, stirring at room temperature for 30min, carrying out suction filtration, washing the filter cake with water, and drying. 1.3g of L-2 is obtained as a yellow solid in yield: 79.8 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ12.82(s,1H),8.53(s,1H),8.50(d,J＝2.2Hz,1H),8.15(dd,J＝9.0,2.3Hz,1H),7.76(d,J＝9.0Hz,1H).ESI-MS:m/z 186.09[M-H]^-.

Preparation of 1-isobutyl-6-nitro-1H-indole-3-carbonitrile (L1-3): adding L-2(1.9g,10mmol), bromoisobutane (1.8g,10.5mmol), potassium carbonate (2.1g,15mmol), potassium iodide (0.12g,0.7mmol) and DMF (30mL) into a reaction bottle, reacting at 60 ℃ for 5 hours, monitoring by TLC, cooling to room temperature after the reaction is finished, adding equivalent water into the reaction liquid, separating out yellow solid, stirring at room temperature for 1 hour, filtering, washing the filter cake with water, and drying. 1.9g of yellow solid L1-3 are obtained, yield: 78.2 percent. M.p 161.1.1-162.3 ℃,¹H NMR(400MHz,DMSO-d₆)δ8.76(d,J＝2.1Hz,1H),8.68(s,1H),8.11(dd,J＝8.8,2.0Hz,1H),7.87(d,J＝8.8Hz,1H),4.27(d,J＝7.5Hz,2H),2.24-2.13(m,1H),0.88(d,J＝6.7Hz,6H).MS:m/z 244.1[M+H]⁺.

preparation of 1-isobutyl-6-amino-1H-indole-3-carbonitrile (L1-4) hydrochloride: adding L1-3(2.0g,12mmol), zinc powder (19.8g,300mmol), ammonium chloride (10.8g,200mmol) and absolute ethyl alcohol (40mL) into a reaction bottle, stirring for 1h at 50 ℃, after TLC monitoring reaction is completed, cooling the reaction liquid to room temperature, carrying out suction filtration, washing a filter cake with water and ethyl acetate, extracting the filtrate with ethyl acetate, washing with water and saturated salt water, drying for 2h by using anhydrous sodium sulfate, carrying out suction filtration to remove inorganic salts, distilling off ethyl acetate under reduced pressure, adding 1N HCl/EA 20mL into the mixture, stirring for 1h at room temperature, separating out a white solid, carrying out suction filtration, washing the filter cake with ethyl acetate, obtaining 1.9g of a white solid L1-4 hydrochloride, and obtaining the yield: 76.3 percent. M.p 246.5.5-247.6 deg.C,¹H NMR(400MHz,DMSO-d₆)δ10.24(s,3H),8.41-8.34(m,1H),7.75(d,J＝8.5Hz,1H),7.70-7.66(m,1H),7.31-7.20(m,1H),4.08(d,J＝7.4Hz,2H),2.19-2.09(m,1H),0.86(d,J＝6.6Hz,6H).MS:m/z 214.1[M+H]⁺.

preparation of N- (3-cyano-1-isobutyl-1H-indol-6-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (L1-5): adding L1-4 hydrochloride (0.6g,2.7mmol), 6-oxo-1, 6-dihydropyrimidine-4-carboxylic acid (0.35g,2.5mmol), HATU (1.24g,3.25mmol), N-diisopropylethylamine (2mL) and DMF (20mL) into a reaction flask, stirring at room temperature for 10h, monitoring the completion of the reaction by TLC, adding a proper amount of water into the reaction flask, adding 1N HCl to adjust the pH to 3-4, precipitating a large amount of yellow solid, continuing stirring for 1h, carrying out suction filtration, washing a filter cake with water, drying, carrying out thermal pulping with tetrahydrofuran for 2h, carrying out suction filtration, carrying out thermal pulping with acetone for 1h, carrying out suction filtration, drying to obtain 0.43g of yellow solid L1-5, wherein the yield is as follows: 51.2 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ13.00(s,1H),10.51(s,1H),8.36(s,1H),8.28(s,1H),8.24(s,1H),7.73(d,J＝8.1Hz,1H),7.60(d,J＝8.6Hz,1H),6.98(s,1H),4.01(d,J＝7.4Hz,2H),2.18(dt,J＝13.7,6.9Hz,1H),0.86(d,J＝6.6Hz,6H).¹³C NMR(101MHz,DMSO-d₆)δ162.08,161.30,154.80,150.73,138.09,135.81,134.63,124.31,119.28,116.49,116.40,114.70,103.75,83.94,54.10,28.92,20.12.ESI-HRMS:Calcd.for C₁₈H₁₇N₅O₂[M–H]^-334.1309,found:334.1312.

Example 5: preparation of N- (3-cyano-1-isopropyl-1H-indol-6-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (L2-5)

According to the preparation method of example 4, 6-nitro-1H-indole-3-carbonitrile (L-2) was obtained.

Preparation of 1-isopropyl-6-nitro-1H-indole-3-carbonitrile (L2-3): adding L-2(1.9g,10mmol), bromoisopropane (1.8g,10.1mmol), potassium carbonate (2.1g,15mmol), potassium iodide (0.12g,0.7mmol) and DMF (30mL) into a reaction bottle, reacting at 60 ℃ for 5h, monitoring by TLC, cooling to room temperature after the reaction is finished, adding an equal amount of water into the reaction liquid, precipitating a yellow solid, stirring at room temperature for 1h, filtering, washing a filter cake with water, and drying. 1.9g of a yellow solid are obtained, yield: 82.6 percent. M.p156.4-157.6 ℃,¹H NMR(400MHz,DMSO-d₆)δ8.86(s,1H),8.75(d,J＝2.0Hz,1H),8.12(dd,J＝8.8,2.0Hz,1H),7.86(d,J＝8.8Hz,1H),5.17–5.07(m,1H),1.53(d,J＝6.6Hz,6H).MS:m/z230.1[M+H]⁺.

preparation of 1-isopropyl-6-amino-1H-indole-3-carbonitrile (L2-4) hydrochloride: adding L2-3(2.0g,11mmol), zinc powder (19.8g,300mmol), ammonium chloride (10.8g,200mmol) and absolute ethyl alcohol (40mL) into a reaction bottle, stirring for 1h at 50 ℃, after TLC monitoring reaction is completed, cooling the reaction liquid to room temperature, carrying out suction filtration, washing a filter cake with water and ethyl acetate, extracting the filtrate with ethyl acetate, washing with water and saturated salt water, drying for 2h by using anhydrous sodium sulfate, carrying out suction filtration to remove inorganic salts, distilling off ethyl acetate under reduced pressure, adding 1N HCl/EA 20mL into the mixture, stirring for 1h at room temperature, separating out a white solid, carrying out suction filtration, washing the filter cake with ethyl acetate, obtaining 1.8g of white solid L2-4 hydrochloride, and obtaining yield: 76.9 percent. M.p 251.3-252.6 ℃ of the total weight of the mixture,¹H NMR(400MHz,DMSO-d₆)δ10.44(s,3H),8.54(s,1H),7.76-7.74(m,2H),7.29(dd,J＝8.5,1.7Hz,1H),4.79(hept,J＝6.6Hz,1H),1.50(d,J＝6.7Hz,6H).MS:m/z 200.0[M+H]⁺.

preparation of N- (3-cyano-1-isopropyl-1H-indol-6-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (L2-5): l2-4 hydrochloride (0.6g,2.6mmol), 6-oxo-1, 6-dihydropyrimidine-4-carboxylic acid (0.35g,2.5mmol), HATU (1.24g,3.25mmol), N-diisopropylethylamine (2mL), DMF (20mL) were added to the reaction flask, stirred at room temperature for 10h, monitored by TLC for completion of the reactionAdding a proper amount of water into a reaction bottle, adding 1N HCl to adjust the pH value to 3-4, separating out a large amount of yellow solid, continuously stirring for 1h, performing suction filtration, washing a filter cake with water, drying, thermally pulping for 2h by using tetrahydrofuran, performing suction filtration, thermally pulping for 1h by using acetone, performing suction filtration, and drying to obtain 0.40g of yellow solid L2-5 with yield: 49.6 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ13.03(s,1H),10.52(s,1H),8.46-8.29(m,3H),7.73(d,J＝8.7Hz,1H),7.63(d,J＝8.6Hz,1H),7.01(s,1H),5.02-4.43(m,1H),1.54(d,J＝6.7Hz,6H).¹³C NMR(101MHz,DMSO-d₆)δ162.06,161.29,154.79,150.72,135.02,134.57,134.52,124.48,119.31,116.58,116.51,114.69,103.59,84.32,48.75,22.46.ESI-HRMS:Calcd.for C₁₇H₁₅N₅O₂[M–H]^-320.1153,found:320.1173.

Example 6: preparation of N- (3-cyano-1-cyclopentyl-1H-indol-5-yl) -2-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Y1-1)

Preparation of 1-cyclopentyl-5-nitro-1H-indole-3-carbonitrile (D10-3): d-2(1.9g,10mmol), bromocyclopentane (1.7g,10.9mmol), potassium carbonate (2.1g,15mmol), potassium iodide (0.12g,0.7mmol) and DMF (30mL) are added into a reaction bottle, the mixture reacts for 5h at 60 ℃, TLC monitoring is carried out, after the reaction is finished, the reaction solution is cooled to room temperature, equal amount of water is added into the reaction solution, yellow solid is separated out, the reaction solution is stirred for 1h at room temperature, and the filter cake is washed by water and dried. 2.0g of D10-3 was obtained as a yellow solid in yield: 78.4 percent. M.p 173.1 between 173.1 and 174.8 ℃,¹H NMR(400MHz,DMSO-d₆)δ8.72(s,1H),8.48(d,J＝2.2Hz,1H),8.18(dd,J＝9.1,2.4Hz,1H),7.98(d,J＝9.2Hz,1H),5.09(p,J＝6.9Hz,1H),2.27-2.20(m,2H),1.92-1.85(m,4H),1.79-1.67(m,2H).MS:m/z 256.1[M+H]⁺.

preparation of 1-cyclopentyl-5-amino-1H-indole-3-carbonitrile (D10-4) hydrochloride: adding D10-3(2.0g,10mmol), zinc powder (19.8g,300mmol), ammonium chloride (10.8g,200mmol) and anhydrous ethanol (40mL) into a reaction bottle, stirring at 50 ℃ for 1h, monitoring reaction by TLC, cooling the reaction solution to room temperature, filtering, washing filter cake with water, washing with ethyl acetate, filtering to obtain filtrateExtracting with ethyl acetate, washing with water, washing with saturated salt water, drying with anhydrous sodium sulfate for 2h, filtering to remove inorganic salts, distilling off ethyl acetate under reduced pressure, adding 1N HCl/EA 20mL, stirring at room temperature for 1h, precipitating a white solid, filtering, washing a filter cake with ethyl acetate to obtain 2.1g of white solid D10-4 hydrochloride, and obtaining the yield: 80.5 percent. M.p 256.1 to 257.3 ℃ of water,¹H NMR(400MHz,DMSO-d₆)δ10.64(s,3H),8.55(s,1H),7.88(d,J＝8.8Hz,1H),7.72(d,J＝2.0Hz,1H),7.39(dd,J＝8.8,2.1Hz,1H),5.01(p,J＝6.9Hz,1H),2.24-2.17(m,2H),1.95-1.80(m,4H),1.76-1.39(m,2H).MS:m/z 226.1[M+H]⁺.

preparation of N- (3-cyano-1-cyclopentyl-1H-indol-5-yl) -2-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxamide (Y1-1): adding D10-4 hydrochloride (0.7g,2.8mmol), 2-methyl-6-oxo-1, 6-dihydropyrimidine-4-carboxylic acid (0.35g,2.5mmol), HATU (1.24g,3.25mmol), N-diisopropylethylamine (2mL) and DMF (20mL) into a reaction flask, stirring at room temperature for 10h, monitoring the reaction by TLC, adding a proper amount of water into the reaction flask, adding 1N HCl to adjust the pH to 3-4, precipitating a large amount of yellow solid, continuously stirring for 1h, carrying out suction filtration, washing a filter cake with water, drying, carrying out thermal pulping for 2h by using tetrahydrofuran, carrying out suction filtration, carrying out thermal pulping for 1h by using acetone, carrying out suction filtration, drying, obtaining 0.55g of white solid Y1-1, and obtaining yield: 60.5 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ12.83(s,1H),10.39(s,1H),8.39(s,1H),8.29(s,1H),7.77–7.65(m,2H),6.80(s,1H),4.98-4.91(m,1H),2.45(s,3H),2.45-2.17(m,2H),1.91–1.83(m,4H),1.77–1.62(m,2H).¹³C NMR(101MHz,DMSO-d₆)δ163.11,161.45,160.45,154.86,135.07,133.27,132.93,127.86,117.86,116.59,112.51,111.46,110.25,84.23,57.91,32.50,23.90,21.67.ESI-HRMS:Calcd.for C₂₀H₁₉N₅O₂[M–H]^-360.1539,found:360.1329.

Example 7: preparation of N- (3-cyano-1-cyclopentyl-1H-indol-5-yl) -2, 6-dioxo-1, 2,3, 6-tetrahydropyrimidine-4-carboxamide (Y1-2)

Following the procedure of example 6, 1-cyclopentyl-5-amino-1H-indole-3-carbonitrile (D10-4) hydrochloride was obtained.

N- (3-cyano-1-cyclopentyl-1H-indol-5-yl) -2,6Preparation of dioxo-1, 2,3, 6-tetrahydropyrimidine-4-carboxamide (Y1-2): adding D10-4 hydrochloride (0.7g,2.8mmol), orotic acid (0.33g,2.4mmol), HATU (1.24g,3.25mmol), N-diisopropylethylamine (2mL) and DMF (20mL) into a reaction flask, stirring at room temperature for 10h, monitoring the reaction by TLC, adding a proper amount of water into the reaction flask after the TLC is completed, adding 1N HCl to adjust the pH to 3-4, precipitating a large amount of yellow solid, continuing stirring for 1h, carrying out suction filtration, washing a filter cake with water, drying, carrying out thermal pulping with tetrahydrofuran for 2h, carrying out suction filtration, carrying out thermal pulping with acetone for 1h, carrying out suction filtration, and drying to obtain 0.61g of yellow solid Y1-2, wherein the yield is: 67.2 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ11.35(s,1H),10.95(s,1H),10.60(s,1H),8.40(s,1H),8.16(s,1H),7.74(d,J＝9.0Hz,1H),7.61(dd,J＝9.0,2.0Hz,1H),6.26(s,1H),4.98–4.91(m,1H),2.28–2.12(m,2H),1.91–1.82(m,4H),1.76–1.67(m,2H).¹³C NMR(101MHz,DMSO-d₆)δ164.60,159.22,151.34,146.08,135.20,133.12(d,J＝18.5Hz),127.87,117.75,116.48,112.66,110.45,100.89,84.26,57.99,32.48,23.91.ESI-HRMS:Calcd.for C₁₉H₁₇N₅O₃[M–H]^-362.1331,found:362.1001.

Example 8: preparation of N- (3-cyano-1-isobutyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D4-5)

Preparation of 1-isobutyl-5-nitro-1H-indole-3-carbonitrile (D4-3): the preparation method is the same as example 1 with bromo-isobutane as the raw material, 1.9g of yellow solid D4-3 is obtained, and the yield is as follows: 78.2 percent. M.p158.1-159.5 ℃,¹H NMR(400MHz,DMSO-d₆)δ8.59(s,1H),8.45(d,J＝2.3Hz,1H),8.16(dd,J＝9.1,2.3Hz,1H),7.96(d,J＝9.2Hz,1H),4.19(d,J＝7.4Hz,2H),2.23-2.12(m,1H),0.89(d,J＝6.7Hz,6H).ESI-MS:m/z 244.1[M+H]⁺.

preparation of 1-isobutyl-5-amino-1H-indole-3-carbonitrile (D4-4) hydrochloride: the preparation method was the same as example 1, using D4-3 as a starting material, to obtain 1.9g of D4-4 hydrochloride as a white solid, with the yield: 76.3 percent. M.p 248.1.1-249.6 deg.c,¹H NMR(400MHz,DMSO-d₆)δ10.65(s,3H),8.44(s,1H),7.87(d,J＝8.8Hz,1H),7.72(d,J＝2.0Hz,1H),7.38(dd,J＝8.8,2.1Hz,1H),4.13(d,J＝7.4Hz,2H),2.20-2.09(m,1H),0.85(d,J＝6.7Hz,6H).MS:m/z 214.1[M+H]⁺.

preparation of N- (3-cyano-1-isobutyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D4-5): the preparation method is the same as example 1 with D4-4 hydrochloride as the raw material, 0.43g yellow solid D4-5 is obtained, yield: 51.2 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ13.02(s,1H),10.52(s,1H),8.38(s,1H),8.34(d,J＝1.9Hz,1H),8.28(s,1H),7.78–7.65(m,2H),6.99(s,1H),4.07(d,J＝7.3Hz,2H),2.15(hept,J＝6.8Hz,1H),0.86(d,J＝6.6Hz,6H).¹³C NMR(101MHz,DMSO-d₆)δ162.06,161.34,154.99,150.74,138.07,133.18,133.12,127.59,118.18,116.45,114.66,112.41,110.46,83.97,54.00,29.26,20.06.ESI-HRMS:Calcd.for C₁₈H₁₇N₅O₂[M–H]^-334.1309,found:334.1311.

Example 9: preparation of N- (3-cyano-1-isopentyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D5-5)

Preparation of 1-isopentyl-5-nitro-1H-indole-3-carbonitrile (D5-3): preparation method example 1 using bromoisopentane as a raw material gave 2.0g of yellow solid with yield: 77.8 percent. M.p 165.1, 165.1-167.0 ℃,¹H NMR(400MHz,DMSO-d₆)δ8.62(s,1H),8.46(d,J＝2.2Hz,1H),8.17(dd,J＝9.1,2.3Hz,1H),7.93(d,J＝9.2Hz,1H),4.36(dd,J＝8.4,6.6Hz,2H),1.74-1.96(m,2H),1.59-1.49(m,1H),0.94(d,J＝6.6Hz,6H).MS:m/z258.1[M+H]⁺.

preparation of 1-isopentyl-5-amino-1H-indole-3-carbonitrile hydrochloride (D5-4): preparation method example 1 using D5-3 as the starting material gave 1.9g of a white solid with yield: 72.2 percent. M.p 235.2.2 to 235.9 ℃,¹H NMR(400MHz,DMSO-d₆)δ10.47(s,3H),8.46(s,1H),7.82(d,J＝8.8Hz,1H),7.68(d,J＝2.0Hz,1H),7.36(dd,J＝8.8,2.1Hz,1H),4.41-4.25(m,1H),1.76-1.61(m,1H),1.49(dp,J＝13.3,6.6Hz,1H),0.92(d,J＝6.6Hz,3H).MS:m/z 228.1[M+H]⁺

preparation of N- (3-cyano-1-isopentyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D5-5): preparation method example 1 starting from D5-4 hydrochloride gave 0.56g of a yellow solid in yield: 64.2 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ12.99(s,1H),10.52(s,1H),8.37(s,1H),8.33(d,J＝1.9Hz,1H),8.31(s,1H),7.73(dd,J＝8.9,2.0Hz,1H),7.67(d,J＝8.9Hz,1H),6.97(s,1H),4.26(t,J＝7.4Hz,2H),1.69(q,J＝7.2Hz,2H),1.50(dp,J＝13.3,6.6Hz,1H),0.92(d,J＝6.6Hz,6H).¹³C NMR(101MHz,DMSO-d₆)δ162.09,161.31,154.95,150.73,137.58,133.21,132.67,127.73,118.18,116.44,114.65,112.11,110.49,84.01,45.34,25.62,22.63.ESI-HRMS:Calcd.for C₁₉H₁₉N₅O₂[M–H]^-348.1446,found:348.1457.

Example 10: preparation of N- (3-cyano-1-allyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D6-5)

Preparation of 1-allyl-5-nitro-1H-indole-3-carbonitrile (D6-3): the preparation method is the same as example 1 with bromopropene as a raw material, and 2.0g of yellow solid is obtained, with the yield: 88.1 percent. M.p 136.1.1-138.2 ℃,¹H NMR(400MHz,DMSO-d₆)δ8.58(s,1H),8.51(d,J＝2.3Hz,1H),8.20(dd,J＝9.1,2.3Hz,1H),7.88(d,J＝9.1Hz,1H),6.10-6.00(m,1H),5.26(d,J＝10.3Hz,1H),5.14(d,J＝16.4Hz,1H),5.04(d,J＝5.4Hz,2H).MS:m/z 228.1[M+H]⁺.

preparation of 1-allyl-5-amino-1H-indole-3-carbonitrile (D6-4) hydrochloride: the preparation method is the same as example 1 with D6-3 as the raw material, 1.5g white solid is obtained, yield: and (4) 64.4%. M.p 245.3.3-246.5 ℃,¹H NMR(400MHz,DMSO-d₆)δ7.98(s,1H),7.27(d,J＝8.7Hz,1H),6.74(d,J＝2.1Hz,1H),6.66(dd,J＝8.8,2.1Hz,1H),6.03-5.93(m,1H),5.19(d,J＝10.2Hz,1H),5.08(d,J＝17.1Hz,1H),4.95(s,2H),4.78(d,J＝5.5Hz,2H).MS:m/z 198.0[M+H]⁺.

preparation of N- (3-cyano-1-allyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D6-5):the preparation method is the same as example 1 with D6-4 hydrochloride as the raw material, 0.45g yellow solid is obtained, yield: 56.4 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ13.00(s,1H),10.51(s,1H),8.38(s,1H),8.36(d,J＝2.0Hz,1H),8.26(s,1H),7.72(dd,J＝9.0,2.0Hz,1H),7.61(d,J＝8.9Hz,1H),6.99(s,1H),6.13-5.89(m,1H),5.24(dd,J＝10.2,1.6Hz,1H),5.13(dd,J＝17.1,1.6Hz,1H),4.92(d,J＝5.5Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ162.07,161.32,154.93,150.71,137.75,133.62,133.32,132.74,127.74,118.37,118.25,116.31,114.66,112.37,110.48,84.40,49.35.ESI-HRMS:Calcd.for C₁₇H₁₃N₅O₂[M–H]^-318.0996,found:318.0978.

Example 11: preparation of N- [ 3-cyano-1- (3-methylbut-2-en-1-yl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D7-5)

Preparation of 1- (3-methylbut-2-en-1-yl) -5-nitro-1H-indole-3-carbonitrile (D7-3): the preparation method is the same as example 1 by using isoamylene bromide as a raw material, 1.9g of yellow solid is obtained, and the yield is as follows: 74.5 percent. M.p 159.2, 159.2 to 160.4 ℃,¹H NMR(400MHz,DMSO-d₆)δ8.54(s,1H),8.47(d,J＝2.2Hz,1H),8.18(dd,J＝9.1,2.3Hz,1H),7.84(d,J＝9.1Hz,1H),5.39(t,J＝7.0Hz,1H),4.96(d,J＝7.1Hz,2H),1.85(s,3H),1.75(s,3H).MS:m/z 256.1[M+H]⁺.

preparation of 1- (3-methylbut-2-en-1-yl) -5-amino-1H-indole-3-carbonitrile (D7-4) hydrochloride: the preparation method is the same as example 1 with D7-3 as a raw material, 1.6g of white solid is obtained, and the yield is as follows: 61.5 percent. M.p 248.1.1-248.9 ℃,¹H NMR(400MHz,DMSO-d₆)δ10.62(s,3H),8.41(s,1H),7.91-7.57(m,2H),7.39(dd,J＝8.7,2.1Hz,1H),5.36(t,J＝7.1Hz,1H),4.90(d,J＝7.1Hz,2H),1.83(d,J＝1.4Hz,3H),1.73(d,J＝1.5Hz,3H).MS:m/z 226.1[M+H]⁺.

n- [ 3-cyano-1- (3-methylbut-2-en-1-yl) -1H-indol-5-yl]-preparation of 6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D7-5): the preparation method of D7-4 hydrochloride used as a raw material is the same as that of example 1, and 0.75g of yellow solid is obtainedThe yield is as follows: 86.4 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ12.99(s,1H),10.52(s,1H),8.37(s,1H),8.33(s,1H),8.24(s,1H),7.72(d,J＝8.9Hz,1H),7.59(d,J＝8.9Hz,1H),6.97(s,1H),5.37(t,J＝7.2Hz,1H),4.84(d,J＝7.1Hz,2H),1.82(s,3H),1.73(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ162.06,161.35,155.01,150.75,137.89,137.32,133.29,132.63,127.87,119.35,118.16,116.41,114.66,112.27,110.46,84.02,44.99,25.79,18.38.ESI-HRMS:Calcd.for C₁₉H₁₇N₅O₂[M–H]^-346.1309,found:346.1294.

Example 12: preparation of N- [ 3-cyano-1- (prop-2-yn-1-yl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D8-5)

Preparation of 1- (prop-2-yn-1-yl) -5-nitro-1H-indole-3-carbonitrile (D8-3): using bromopropyne as a raw material, the preparation method was the same as example 1, and 1.7g of a yellow solid was obtained, with the yield: 75.6 percent. M.p 169.2 is between 169.2 and 170.5 ℃,¹H NMR(400MHz,DMSO-d₆)δ8.62(s,1H),8.53(d,J＝2.2Hz,1H),8.27(dd,J＝9.1,2.3Hz,1H),7.96(d,J＝9.1Hz,1H),5.34(d,J＝2.6Hz,2H),3.62(t,J＝2.5Hz,1H).MS:m/z 226.0[M+H]⁺.

preparation of 1- (prop-2-yn-1-yl) -5-amino-1H-indole-3-carbonitrile (D8-4) hydrochloride: the preparation method is the same as example 1 with D8-3 as the raw material, 1.1g white solid is obtained, yield: and (4) 64.9%. M.p 255.3-256.5 ℃ of water,¹H NMR(400MHz,DMSO-d₆)δ10.65(s,3H),8.49(s,1H),7.85(d,J＝8.8Hz,1H),7.75(d,J＝2.0Hz,1H),7.44(dd,J＝8.8,2.0Hz,1H),5.29(d,J＝2.6Hz,2H),3.59(t,J＝2.5Hz,1H).MS:m/z 196.0[M+H]⁺.

n- [ 3-cyano-1- (prop-2-yn-1-yl) -1H-indol-5-yl]Preparation of 6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D8-5) starting from D8-4 hydrochloride the procedure is as in example 1 to give 0.45 yellow solid in yield: 56.8 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ12.93(s,1H),10.55(s,1H),8.38(s,1H),8.36(d,J＝1.9Hz,1H),8.32(s,1H),7.78(dd,J＝8.9,2.0Hz,1H),7.70(d,J＝8.9Hz,1H),6.98(s,1H),5.22(d,J＝2.5Hz,2H),3.54(d,J＝2.6Hz,1H).¹³C NMR(101MHz,DMSO-d₆)δ162.20,161.44,154.93,150.83,137.36,133.63,132.38,127.75,118.48,116.03,114.65,112.35,110.55,84.98,78.32,77.31,36.66.ESI-HRMS:Calcd.for C₁₇H₁₁N₅O₂[M–H]^-316.0840,found:316.0834.

Example 13: preparation of N- [ 3-cyano-1- (cyclopropylmethyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D9-5)

Preparation of 1- (cyclopropylmethyl) -5-nitro-1H-indole-3-carbonitrile (D9-3): the preparation method is the same as example 1 with bromomethylcyclopropane as the raw material, and 1.8g of yellow solid is obtained, with the yield: 75.1 percent. M.p154.6-155.8 ℃,¹H NMR(400MHz,DMSO-d₆)δ8.65(s,1H),8.45(d,J＝2.2Hz,1H),8.16(dd,J＝9.1,2.3Hz,1H),7.97(d,J＝9.1Hz,1H),4.23(d,J＝7.2Hz,2H),1.38-1.28(m,1H),0.72-0.39(m,4H).MS:m/z 242.1[M+H]⁺.

preparation of 1- (cyclopropylmethyl) -5-amino-1H-indole-3-carbonitrile hydrochloride (D9-4): the preparation method is the same as example 1 with D9-3 as the raw material, 1.8g of white solid is obtained, and the yield is as follows: 72.9 percent. M.p 245.6.6-247.1 deg.C,¹H NMR(400MHz,DMSO-d6)δ10.62(s,3H),8.51(s,1H),7.88(d,J＝8.8Hz,1H),7.72(d,J＝1.9Hz,1H),7.39(dd,J＝8.8,2.0Hz,1H),4.18(d,J＝7.2Hz,2H),1.33-1.24(m,1H),0.62-0.39(m,4H).MS:m/z212.1[M+H]⁺.

n- [ 3-cyano-1- (cyclopropylmethyl) -1H-indol-5-yl]-preparation of 6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D9-5): the preparation method is the same as example 1 with D9-4 hydrochloride as the raw material, 0.55g yellow solid is obtained, yield: 66.7 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ12.95(s,1H),10.53(s,1H),8.37(s,1H),8.34(d,J＝5.5Hz,2H),7.72(s,2H),6.97(s,1H),4.12(d,J＝7.1Hz,2H),1.34-1.26(m,1H),0.58-0.35(m,4H).¹³C NMR(101MHz,DMSO-d₆)δ162.10,161.37,155.02,150.78,137.49,133.26,132.88,127.70,118.16,116.49,114.64,112.32,110.40,83.99,51.15,11.68,4.25.ESI-HRMS:Calcd.for C₁₈H₁₅N₅O₂[M–H]^-332.1153,found:332.1167.

Example 14: preparation of N- (3-cyano-1-cyclopentyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D10-5)

Preparation of N- (3-cyano-1-cyclopentyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D10-5): the preparation method is the same as example 1 with D10-4 hydrochloride as the raw material, 0.45g yellow solid is obtained, yield: 51.6 percent. M.p>290℃¹H NMR(400MHz,DMSO-d₆)δ12.99(s,1H),10.52(s,1H),8.38(d,J＝2.1Hz,2H),8.33(d,J＝1.8Hz,1H),7.79-7.66(m,2H),6.98(s,1H),4.94(p,J＝6.9Hz,1H),2.26-2.15(m,2H),1.92-1.67(m,6H).¹³C NMR(101MHz,DMSO-d₆)δ162.07,161.34,155.00,150.74,135.03,133.31,132.94,127.85,118.06,116.55,114.65,112.48,110.40,84.29,57.94,32.48,23.92.ESI-HRMS:Calcd.for C₁₉H₁₇N₅O₂[M–H]^-346.1309,found:346.1312.

Example 15: preparation of N- [ 3-cyano-1- (cyclohexylmethyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D11-5)

Preparation of 1- (cyclohexylmethyl) -5-nitro-1H-indole-3-carbonitrile (D11-3): the preparation method is the same as example 1 with bromomethylcyclohexane as a raw material, and 2.2g of yellow solid is obtained, with the yield: 77.7 percent. M.p 149.1.1-150.1 deg.C,¹H NMR(400MHz,DMSO-d₆)δ8.57(s,1H),8.46(d,J＝2.2Hz,1H),8.17(dd,J＝9.1,2.3Hz,1H),7.97(d,J＝9.2Hz,1H),4.22(d,J＝7.3Hz,2H),1.90-1.81(m,1H),1.74-0.87(m,10H).MS:m/z 284.1[M+H]⁺.

preparation of 1- (cyclohexylmethyl) -5-amino-1H-indole-3-carbonitrile (D11-4) hydrochloride: the preparation method is the same as example 1 with D11-3 as the raw material, 2.3g of white solid is obtained, and the yield is as follows: 91.1 percent. M.p 243.1.1-244.5 ℃,¹H NMR(400MHz,DMSO-d₆)δ7.95(s,1H),7.33(d,J＝8.7Hz,1H),6.74(d,J＝2.1Hz,1H),6.67(dd,J＝8.8,2.0Hz,1H),4.94(s,2H),3.95(d,J＝7.2Hz,2H),1.79-1.73(m,1H),1.69-1.34(m,5H),1.16-0.89(m,5H).MS:m/z 254.1[M+H]⁺.

n- [ 3-cyano-1- (cyclohexylmethyl) -1H-indol-5-yl]-preparation of 6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D11-5): the preparation method is the same as example 1 with D11-4 hydrochloride as the raw material, 0.45g yellow solid is obtained, yield: 48.6 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ12.98(s,1H),10.52(s,1H),8.37(s,1H),8.31(s,1H),8.26(s,1H),7.84-7.55(m,2H),6.96(s,1H),4.10(d,J＝7.3Hz,2H),1.83-1.81(m,1H),1.68-1.42(m,5H),1.16-0.94(m,5H).¹³C NMR(151MHz,DMSO-d₆)δ162.05,161.36,155.02,150.76,138.22,133.19,133.16,127.56,112.49,110.45,83.83,52.83,38.35,30.37,26.27,25.55.ESI-HRMS:Calcd.for C₂₁H₂₁N₅O₂[M–H]^-374.1622,found:374.1634.

Example 16: preparation of N- (3-cyano-1-benzyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D12-5)

Preparation of 1-benzyl-5-nitro-1H-indole-3-carbonitrile (D12-3): benzyl chloride was used as a raw material, and the preparation method was the same as in example 1, to obtain 2.5g of a yellow solid, yield: 90.3 percent. M.p 201.1.1-202.7 ℃,¹H NMR(400MHz,DMSO-d₆)δ8.76(s,1H),8.51(d,J＝2.3Hz,1H),8.17(dd,J＝9.1,2.3Hz,1H),7.91(d,J＝9.1Hz,1H),7.48-7.25(m,5H),5.64(s,2H).MS:m/z 278.1[M+H]⁺.

preparation of 1-benzyl-5-amino-1H-indole-3-carbonitrile (D12-4) hydrochloride: the preparation method is the same as example 1 with D12-3 as the raw material, 2.3g of white solid is obtained, and the yield is as follows: 82.1 percent. M.p 251.3-253.0 ℃ of the total weight of the mixture,¹H NMR(400MHz,DMSO-d₆)δ10.29(s,3H),8.59(s,1H),7.76(d,J＝8.8Hz,1H),7.66(d,J＝2.0Hz,1H),7.41-7.19(m,6H),5.56(s,2H).MS:m/z 248.1[M+H]⁺.

n- (3-cyano-1-benzyl-1H-indol-5-yl) -6-oxo-Preparation of 1, 6-dihydropyrimidine-4-carboxamide (D12-5): the preparation method is the same as example 1 with D12-4 hydrochloride as the raw material, 0.45g yellow solid is obtained, yield: 48.8 percent. M.p>290℃¹H NMR(400MHz,DMSO-d₆)δ13.02(s,1H),10.52(s,1H),8.46(s,1H),8.37(d,J＝1.1Hz,1H),8.35(d,J＝1.9Hz,1H),7.68(dd,J＝9.0,2.0Hz,1H),7.63(d,J＝9.0Hz,1H),7.37-7.27(m,5H),6.97(d,J＝1.0Hz,1H),5.51(s,2H).¹³C NMR(101MHz,DMSO-d₆)δ162.05,161.39,154.97,150.76,138.14,137.13,133.40,132.70,129.21,128.31,127.86,127.75,118.40,116.28,114.69,112.53,110.56,84.58,50.45.ESI-HRMS:Calcd.for C₂₁H₁₅N₅O₂[M–H]^-368.1153,found:368.1156.

Example 17: preparation of N- [ 3-cyano-1- (4-methylbenzyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D13-5)

Preparation of 1- (4-methylbenzyl) -5-nitro-1H-indole-3-carbonitrile (D13-3): the preparation method is the same as example 1 by using 4-methylbenzyl chloride as a raw material, and 2.4g of yellow solid is obtained, wherein the yield is as follows: 82.8 percent. M.p 191.2, 191.2 to 192.7 ℃,¹H NMR(400MHz,DMSO-d₆)δ8.73(s,1H),8.50(d,J＝2.2Hz,1H),8.16(dd,J＝9.1,2.3Hz,1H),7.90(d,J＝9.1Hz,1H),7.23(d,J＝7.9Hz,2H),7.16(d,J＝7.9Hz,2H),5.57(s,2H),2.26(s,3H).MS:m/z292.1[M+H]⁺.

preparation of 1- (4-methylbenzyl) -5-amino-1H-indole-3-carbonitrile (D13-4) hydrochloride: the preparation method is the same as example 1 with D13-3 as the raw material, 2.4g of white solid is obtained, and the yield is as follows: 80.8 percent. M.p 256.3.3-258.1 ℃,¹H NMR(400MHz,DMSO-d₆)δ10.52(s,3H),8.59(s,1H),7.77(d,J＝8.8Hz,1H),7.70(d,J＝2.0Hz,1H),7.32(dd,J＝8.8,2.0Hz,1H),7.20(d,J＝8.1Hz,2H),7.14(d,J＝7.8Hz,2H),5.50(s,2H),2.24(s,3H).MS:m/z 262.1[M+H]⁺.

n- [ 3-cyano-1- (4-methylbenzyl) -1H-indol-5-yl]-preparation of 6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D13-5): the preparation method is the same as example 1 with D13-4 hydrochloride as the raw material, 0.47g yellow solid is obtained, and the yield is high：48.8％。M.p281.5-283.1℃，¹H NMR(400MHz,DMSO-d₆)δ10.50(s,1H),8.43(s,1H),8.38(d,J＝8.8Hz,2H),7.66(d,J＝9.1Hz,1H),7.61(d,J＝8.9Hz,1H),7.20(d,J＝7.8Hz,2H),7.14(d,J＝7.8Hz,2H),6.93(s,1H),5.45(s,2H),2.25(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ162.07,154.87,137.99,137.61,134.07,133.50,132.55,129.73,127.91,127.81,118.24,116.35,113.07,112.56,110.28,84.43,50.27,21.11.ESI-HRMS:Calcd.for C₂₂H₁₇N₅O₂[M–H]^-382.1309,found:382.1314.

Example 18: preparation of N- [ 3-cyano-1- (4-methoxybenzyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D14-5)

Preparation of 1- (4-methoxybenzyl) -5-nitro-1H-indole-3-carbonitrile (D14-3): the preparation method is the same as example 1 by using 4-methoxybenzyl chloride as a raw material, so that 2.7g of yellow solid is obtained, and the yield is as follows: 87.9 percent. M.p 132.1.1-133.5 deg.C¹H NMR(400MHz,DMSO-d₆)δ8.74(s,1H),8.51(d,J＝2.2Hz,1H),8.17(dd,J＝9.1,2.2Hz,1H),7.94(d,J＝9.1Hz,1H),7.31(d,J＝8.7Hz,2H),6.91(d,J＝8.7Hz,2H),5.54(s,2H),3.71(s,3H).MS:m/z308.1[M+H]⁺.

Preparation of 1- (4-methoxybenzyl) -5-amino-1H-indole-3-carbonitrile (D14-4) hydrochloride: the preparation method was the same as example 1 using 1- (4-methoxybenzyl) -5-nitro-1H-indole-3-carbonitrile (D14-3) as a starting material to give 2.8g of a white solid with yield: 89.5 percent. M.p 245.6.6-246.3 ℃,¹H NMR(400MHz,DMSO-d₆)δ10.63(s,3H),8.60(s,1H),7.83(d,J＝8.8Hz,1H),7.73(d,J＝2.0Hz,1H),7.36(dd,J＝8.8,2.0Hz,1H),7.30(d,J＝8.7Hz,2H),6.89(d,J＝8.6Hz,2H),5.48(s,2H),3.71(s,3H).MS:m/z 278.1[M+H]⁺.

n- [ 3-cyano-1- (4-methoxybenzyl) -1H-indol-5-yl]-preparation of 6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D14-5): the preparation method is the same as example 1 with D14-4 hydrochloride as the raw material, 0.43 yellow solid is obtained, yield: 43.2 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ13.02(s,1H),10.51(s,1H),8.42(s,1H),8.38(dd,J＝6.5,1.5Hz,2H),7.70(dd,J＝9.0,2.0Hz,1H),7.65(d,J＝9.0Hz,1H),7.29(d,J＝8.7Hz,2H),7.01(d,J＝1.0Hz,1H),6.91(d,J＝8.7Hz,2H),5.42(s,2H),3.72(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ162.09,161.32,159.39,154.90,150.69,137.84,133.32,132.59,129.36,128.90,127.94,118.29,116.33,114.70,114.57,112.51,110.53,84.48,55.52,50.02.ESI-HRMS:Calcd.for C₂₂H₁₇N₅O₃[M–H]^-398.1259,found:398.1254.

Example 19: preparation of N- [ 3-cyano-1- (4-tert-butylbenzyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D15-5)

Preparation of 1- (4-tert-butylbenzyl) -5-nitro-1H-indole-3-carbonitrile (D15-3): the preparation method is the same as example 1 by using 4-tert-butyl benzyl chloride as a raw material, and 3.1g of yellow solid is obtained, wherein the yield is as follows: 93.1 percent. M.p 139.1.1-140.5 ℃,¹H NMR(400MHz,DMSO-d₆)δ8.75(s,1H),8.52(d,J＝2.2Hz,1H),8.18(dd,J＝9.1,2.3Hz,1H),7.95(d,J＝9.1Hz,1H),7.36(d,J＝8.4Hz,2H),7.25(d,J＝8.4Hz,2H),5.58(s,2H),1.22(s,9H).MS:m/z334.2[M+H]⁺.

preparation of 1- (4-tert-butylbenzyl) -5-amino-1H-indole-3-carbonitrile (D15-4) hydrochloride: the preparation method is the same as example 1 with D15-3 as a raw material, 3.1g of white solid is obtained, and the yield is as follows: 91.4 percent. M.p 236.3.3 to 237.5 ℃,¹H NMR(400MHz,DMSO-d₆)δ10.45(s,3H),8.60(s,1H),7.81(d,J＝8.8Hz,1H),7.69(d,J＝2.0Hz,1H),7.37-7.30(m,3H),7.22(d,J＝8.4Hz,2H),5.51(s,2H),1.22(s,9H).MS:m/z 304.2[M+H]⁺.

n- [ 3-cyano-1- (4-tert-butylbenzyl) -1H-indol-5-yl]-preparation of 6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D15-5): using D15-4 hydrochloride as a starting material, the preparation method was the same as example 1, giving 0.56g of a yellow solid, yield: 52.7 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ12.74(s,1H),10.52(s,1H),8.46(s,1H),8.35(d,J＝9.9Hz,2H),7.67(d,J＝2.6Hz,2H),7.35(d,J＝7.9Hz,2H),7.23(d,J＝8.0Hz,2H),6.96(s,1H),5.46(s,2H),1.23(s,9H).¹³C NMR(151MHz,DMSO-d₆)δ162.19,161.40,154.95,150.85,150.76,138.07,134.19,133.38,132.67,127.83,127.55,125.95,118.38,116.32,114.62,112.57,110.51,84.47,50.08,34.70,31.50.ESI-HRMS:Calcd.for C₂₅H₂₂N₅O₂[M–H]^-424.1779,found:424.1791.

Example 20: preparation of N- [ 3-cyano-1- (4-fluorobenzyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D16-5)

Preparation of 1- (4-fluorobenzyl) -5-nitro-1H-indole-3-carbonitrile (D16-3): the preparation method is the same as example 1 by using 4-fluorobenzyl chloride as a raw material, so that 2.8g of yellow solid is obtained, and the yield is as follows: 94.9 percent. M.p 223.5.5 to 225.1 ℃,¹H NMR(400MHz,DMSO-d₆)δ8.75(s,1H),8.52(d,J＝2.2Hz,1H),8.18(dd,J＝9.1,2.2Hz,1H),7.94(d,J＝9.2Hz,1H),7.42-7.38(m,2H),7.21-7.17(m,2H),5.62(s,2H).MS:m/z 296.1[M+H]⁺.

preparation of 1- (4-fluorobenzyl) -5-amino-1H-indole-3-carbonitrile (D16-4) hydrochloride salt: the preparation method of D16-3 as the raw material is the same as that of example 1, and 2.7g of white solid is obtained, with the yield: 89.7 percent. M.p 256.3, 256.3 to 257.4 ℃,¹H NMR(400MHz,DMSO-d₆)δ10.50(s,3H),8.61(s,1H),7.81(d,J＝8.8Hz,1H),7.70(d,J＝2.0Hz,1H),7.40-7.35(m,2H),7.33(dd,J＝8.8,2.1Hz,1H),7.21-7.13(m,2H),5.56(s,2H).MS:m/z 266.1[M+H]⁺.

n- [ 3-cyano-1- (4-fluorobenzyl) -1H-indol-5-yl]-preparation of 6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D16-5): using D16-4 hydrochloride as a starting material, preparation was carried out in the same manner as in example 1 to give a yellow solid in an amount of 0.35g, yield: 36.7 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ13.00(s,1H),10.53(s,1H),8.46(s,1H),8.37(d,J＝6.0Hz,2H),7.71(dd,J＝8.9,2.0Hz,1H),7.65(d,J＝8.9Hz,1H),7.38(dd,J＝8.4,5.4Hz,2H),7.18(t,J＝8.7Hz,2H),6.99(s,1H),5.51(s,2H).¹³C NMR(101MHz,DMSO-d₆)δ163.38,162.08,161.37,160.95,154.93,150.74,138.00,133.43,133.32,133.29,132.59,130.05,129.97,127.89,118.43,116.24,116.13,115.92,114.69,112.47,110.58,84.71,49.69.ESI-HRMS:Calcd.for C₂₁H₁₄FN₅O₂[M–H]^-386.1059,found:386.1058.

Example 21: preparation of N- [ 3-cyano-1- (4-chlorobenzyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D17-5)

Preparation of 1- (4-chlorobenzyl) -5-nitro-1H-indole-3-carbonitrile (D17-3): the preparation method of p-4-chlorobenzyl chloride used as a raw material is the same as that of example 1, 3.0g of yellow solid is obtained, and the yield is as follows: 96.5 percent. M.p 186.1.1-187.4 ℃,¹H NMR(400MHz,DMSO-d₆)δ8.76(s,1H),8.51(d,J＝2.3Hz,1H),8.18(dd,J＝9.1,2.3Hz,1H),7.91(d,J＝9.1Hz,1H),7.43(d,J＝8.2Hz,2H),7.37(d,J＝8.3Hz,2H),5.65(s,2H).MS:m/z 312.0[M+H]⁺.

preparation of 1- (4-chlorobenzyl) -5-amino-1H-indole-3-carbonitrile hydrochloride (D17-4): the preparation method of D17-3 as the raw material is the same as that of example 1, 3.0g of white solid is obtained, and the yield is as follows: 94.3 percent. M.p 258.3.3 to 259.1 ℃ in percentage by weight,¹H NMR(400MHz,DMSO-d₆)δ10.52(s,3H),8.62(s,1H),7.78(d,J＝8.8Hz,1H),7.72(d,J＝2.0Hz,1H),7.40(d,J＝8.4Hz,2H),7.36-7.29(m,3H),5.58(s,2H).MS:m/z 282.0[M+H]⁺.

n- [ 3-cyano-1- (4-chlorobenzyl) -1H-indol-5-yl]-preparation of 6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D17-5): the preparation method is the same as example 1 with D17-4 hydrochloride as the raw material, 0.39g yellow solid is obtained, yield: 38.8 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ12.98(s,1H),10.52(d,J＝3.1Hz,1H),8.46(d,J＝1.4Hz,1H),8.35(d,J＝7.7Hz,2H),7.71-7.65(m,1H),7.62(dd,J＝8.9,3.2Hz,1H),7.45–7.25(m,5H),6.96(s,1H),5.51(s,2H).¹³C NMR(101MHz,DMSO-d₆)δ162.06,161.39,154.97,150.77,138.14,137.13,136.14,133.40,132.70,129.67,129.21,128.32,127.86,127.75,118.40,116.27,114.68,112.53,84.58,50.45.ESI-HRMS:Calcd.for C₂₁H₁₄ClN₅O₂[M–H]^-402.0763,found:402.0779.

Example 22: preparation of N- [ 3-cyano-1- (4-bromobenzyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D18-5)

Preparation of 1- (4-bromobenzyl) -5-nitro-1H-indole-3-carbonitrile (D18-3): the preparation method of p-4-bromobenzyl bromide used as a raw material is the same as that of example 1, and 3.1g of yellow solid is obtained, with the yield: 87.1 percent. M.p 179.8-180.1 ℃ of the total weight of the mixture,¹H NMR(400MHz,DMSO-d₆)δ8.75(s,1H),8.52(d,J＝2.3Hz,1H),8.18(dd,J＝9.1,2.3Hz,1H),7.90(d,J＝9.1Hz,1H),7.56(d,J＝8.1Hz,2H),7.28(d,J＝8.1Hz,2H),5.62(s,2H).MS:m/z 356.0[M+H]⁺.

preparation of 1- (4-bromobenzyl) -5-amino-1H-indole-3-carbonitrile (D18-4) hydrochloride salt: the preparation method is the same as example 1 with D18-3 as a raw material, 3.0g of white solid is obtained, and the yield is as follows: 83.3 percent. M.p 257.9-259.0 ℃ of the mixture,¹H NMR(400MHz,DMSO-d₆)δ10.57(s,3H),8.63(s,1H),7.79(d,J＝8.8Hz,1H),7.74(d,J＝2.0Hz,1H),7.53(d,J＝8.4Hz,2H),7.36(dd,J＝8.8,2.1Hz,1H),7.26(d,J＝8.4Hz,2H),5.57(s,2H).MS:m/z 326.0[M+H]⁺.

n- [ 3-cyano-1- (4-bromobenzyl) -1H-indol-5-yl]-preparation of 6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D18-5): the preparation method is the same as example 1 with D18-4 hydrochloride as the raw material, 0.51g yellow solid is obtained, yield: 45.6 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ13.01(s,1H),10.53(s,1H),8.46(s,1H),8.37(dd,J＝4.2,1.5Hz,2H),7.70(dd,J＝9.0,2.0Hz,1H),7.62(d,J＝9.0Hz,1H),7.54(d,J＝8.4Hz,2H),7.25(d,J＝8.5Hz,2H),6.99(s,1H),5.50(s,2H).¹³C NMR(101MHz,DMSO-d₆)δ162.06,161.37,154.93,150.73,138.09,136.52,133.47,132.61,132.12,129.96,127.87,121.52,118.47,116.21,114.71,112.44,110.59,84.82,49.77.ESI-HRMS:Calcd.for C₂₁H₁₄BrN₅O₂[M–H]^-446.0258,found:446.0257.

Example 23: preparation of N- [ 3-cyano-1- (3-fluorobenzyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D19-5)

Preparation of 1- (3-fluorobenzyl) -5-nitro-1H-indole-3-carbonitrile (D19-3): the preparation method is the same as example 1 by using 3-fluorobenzyl chloride as a raw material, so that 2.5g of yellow solid is obtained, and the yield is as follows: 84.7 percent. M.p 172.1.1-173.1 deg.C,¹H NMR(400MHz,DMSO-d₆)δ8.78(s,1H),8.51(d,J＝2.2Hz,1H),8.19(dd,J＝9.2,2.3Hz,1H),7.94(d,J＝9.2Hz,1H),7.43(q,J＝6.4Hz,1H),7.25(d,J＝9.9,2.1Hz,1H),7.21-7.10(m,2H),5.68(s,2H).MS:m/z296.1[M+H]⁺.

preparation of 1- (3-fluorobenzyl) -5-amino-1H-indole-3-carbonitrile (D19-4) hydrochloride salt: the preparation method is the same as example 1 with D19-3 as the raw material, 2.7g of white solid is obtained, and the yield is as follows: 89.7 percent. M.p 256.3.3-257.3 deg.C¹H NMR(400MHz,DMSO-d₆)δ10.56(s,3H),8.64(s,1H),7.81(d,J＝8.8Hz,1H),7.73(d,J＝2.0Hz,1H),7.44-7.30(m,2H),7.20(dd,J＝10.0,2.0Hz,1H),7.17-7.08(m,2H),5.60(s,2H).MS:m/z 266.1[M+H]⁺.

N- [ 3-cyano-1- (3-fluorobenzyl) -1H-indol-5-yl]-preparation of 6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D19-5): the preparation method is the same as example 1 with D19-4 hydrochloride as the raw material, 0.38g yellow solid is obtained, yield: 38.7 percent. M.p>290℃，¹H NMR(600MHz,DMSO-d₆)δ10.56(s,1H),8.50(s,1H),8.40(d,J＝4.7Hz,2H),7.72(d,J＝9.0Hz,1H),7.67(d,J＝9.0Hz,1H),7.40(d,J＝7.3Hz,1H),7.20(d,J＝9.9Hz,1H),7.13(d,J＝8.2Hz,2H),7.00(s,1H),5.55(s,2H).¹³C NMR(151MHz,DMSO-d₆)δ163.50,162.52,161.88,161.46,154.88,151.01,139.92,139.87,138.15,133.50,132.60,131.30,131.24,127.83,123.82,118.48,116.25,115.25,115.12,114.80,114.65,114.53,112.44,110.55,84.82,49.83.ESI-HRMS:Calcd.for C₂₁H₁₄FN₅O₂[M–H]^-386.1059,found:386.1058.

Example 24: preparation of N- [ 3-cyano-1- (3-chlorobenzyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D20-5)

1-(3-Preparation of chlorobenzyl) -5-nitro-1H-indole-3-carbonitrile (D20-3): the preparation method is the same as example 1 by using 3-chlorobenzyl chloride as a raw material to obtain 2.6g of yellow solid, wherein the yield is as follows: 83.6 percent. M.p 180.2.2-181.5 ℃ of water,¹H NMR(400MHz,DMSO-d₆)δ8.78(s,1H),8.51(d,J＝2.2Hz,1H),8.19(dd,J＝9.2,2.3Hz,1H),7.95(d,J＝9.2Hz,1H),7.49(s,1H),7.42-7.37(m,2H),7.32-7.25(m,1H),5.66(s,2H).MS:m/z 312.0[M+H]⁺.

preparation of 1- (3-chlorobenzyl) -5-amino-1H-indole-3-carbonitrile (D20-4) hydrochloride: the preparation method is the same as example 1 with D20-3 as a raw material, 3.0g of white solid is obtained, and the yield is as follows: 94.3 percent. M.p 257.1-258.6 ℃ of the total weight of the composition,¹H NMR(400MHz,DMSO-d₆)δ10.51(s,3H),8.63(s,1H),7.81(d,J＝8.8Hz,1H),7.72(d,J＝2.0Hz,1H),7.43(s,1H),7.38-7.32(m,3H),7.24-7.21(m,1H),5.59(s,2H).MS:m/z 282.0[M+H]⁺.

n- [ 3-cyano-1- (3-chlorobenzyl) -1H-indol-5-yl]-preparation of 6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D20-5): the preparation method is the same as example 1 with D20-4 hydrochloride as the raw material, 0.44g yellow solid is obtained, yield: 43.6 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ12.98(s,1H),10.53(s,1H),8.48(s,1H),8.38-8.29(m,2H),7.70(dd,J＝9.0,1.9Hz,1H),7.65(d,J＝9.0Hz,1H),7.42(s,1H),7.37(dd,J＝4.7,1.9Hz,2H),7.28-7.15(m,1H),6.96(s,1H),5.53(s,2H).¹³C NMR(151MHz,DMSO-d₆)δ162.09,161.41,154.95,150.79,139.61,138.19,133.80,133.52,132.59,131.17,128.35,127.81,127.71,126.46,118.53,116.22,114.70,112.46,110.58,84.82,49.71.ESI-HRMS:Calcd.for C₂₁H₁₄ClN₅O₂[M–H]^-402.0763,found:402.0760.

Example 25: preparation of N- [ 3-cyano-1- (2-fluorobenzyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D21-5)

Preparation of 1- (2-fluorobenzyl) -5-nitro-1H-indole-3-carbonitrile (D21-3): the preparation method is the same as example 1 by using 2-fluorobenzyl chloride as a raw material to obtain 2.5g of yellow solid, wherein the yield is as follows: 84.7 percent. M.p 192.4.4-193.7 deg.C,¹H NMR(400MHz,DMSO-d₆)δ8.68(s,1H),8.53(d,J＝2.2Hz,1H),8.20(dd,J＝9.2,2.3Hz,1H),7.92(d,J＝9.2Hz,1H),7.43-7.37(m,1H),7.31–7.15(m,3H),5.70(s,2H).MS:m/z 296.1[M+H]⁺.

preparation of 1- (2-fluorobenzyl) -5-amino-1H-indole-3-carbonitrile (D21-4) hydrochloride salt: the preparation method is the same as example 1 with D21-3 as the raw material, 2.6g of white solid is obtained, and the yield is as follows: 86.4 percent. M.p 259.0.0 to 259.6 ℃,¹H NMR(400MHz,DMSO-d₆)δ10.65(s,3H),8.56(s,1H),7.80(d,J＝8.8Hz,1H),7.76(d,J＝2.0Hz,1H),7.43-7.34(m,2H),7.29-7.14(m,3H),5.65(s,2H).MS:m/z 266.1[M+H]⁺.

n- [ 3-cyano-1- (2-fluorobenzyl) -1H-indol-5-yl]-preparation of 6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D21-5): using D21-4 hydrochloride as a starting material, the preparation method was the same as example 1, yielding 0.38g of a yellow solid: 38.7 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ13.02(s,1H),10.53(s,1H),8.39(s,3H),7.72(dd,J＝8.9,2.0Hz,1H),7.64(d,J＝8.9Hz,1H),7.41-7.35(m,1H),7.29-7.14(m,3H),7.01(s,1H),5.59(s,2H).¹³C NMR(151MHz,DMSO-d₆)δ162.09,161.32(d,J＝7.7Hz),159.67,154.89,150.71,138.18,133.47,132.67,130.78,130.73,130.21,130.19,127.72,125.29,125.28,123.94,123.84,118.48,116.18,116.16,116.02,114.72,112.20,110.58,84.90,44.71.ESI-HRMS:Calcd.for C₂₁H₁₄FN₅O₂[M–H]^-386.1059,found:386.1070.

Example 26: preparation of N- (3-cyano-1-isopropyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D3-5)

Preparation of 1- (2-chlorobenzyl) -5-nitro-1H-indole-3-carbonitrile (D22-3): the preparation method is the same as example 1 by using 2-chlorobenzyl chloride as a raw material to obtain 2.6g of yellow solid, wherein the yield is as follows: 83.6 percent. M.p 167.1.1-168.2 deg.C,¹H NMR(400MHz,DMSO-d₆)δ8.63(s,1H),8.52(d,J＝2.2Hz,1H),8.17(dd,J＝9.1,2.3Hz,1H),7.86(d,J＝9.1Hz,1H),7.55(d,J＝6.5Hz,1H),7.39(t,J＝7.7Hz,1H),7.32(t,J＝6.8Hz,1H),6.99(d,J＝5.9Hz,1H),5.73(s,2H).MS:m/z 312.0[M+H]⁺.

preparation of 1- (2-chlorobenzyl) -5-amino-1H-indole-3-carbonitrile (D22-4) hydrochloride: the preparation method is the same as example 1 with D22-3 as the raw material, 2.8g of white solid is obtained, and the yield is as follows: 88.3 percent. M.p 256.3, 256.3 to 257.4 ℃,¹H NMR(400MHz,DMSO-d₆)δ10.53(s,3H),8.49(s,1H),7.75-7.70(m,2H),7.53(dd,J＝7.9,1.3Hz,1H),7.38-7.26(m,3H),6.89(dd,J＝7.7,1.7Hz,1H),5.66(s,2H).MS:m/z 282.0[M+H]⁺.

n- [ 3-cyano-1- (2-chlorobenzyl) -1H-indol-5-yl]-preparation of 6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D22-5): the preparation method is the same as example 1 with D22-4 hydrochloride as the raw material, 0.42g yellow solid is obtained, yield: 43.3 percent. M.p>290℃¹H NMR(400MHz,DMSO-d₆)δ13.01(s,1H),10.52(s,1H),8.42-8.36(m,2H),8.34(s,1H),7.70(dd,J＝9.0,2.0Hz,1H),7.59-7.49(m,2H),7.36(td,J＝7.6,1.7Hz,1H),7.29(td,J＝7.5,1.4Hz,1H),7.00(d,J＝1.1Hz,1H),6.91(dd,J＝7.6,1.8Hz,1H),5.60(s,2H).¹³C NMR(151MHz,DMSO-d₆)δ162.08,161.35,154.88,150.71,138.37,134.27,133.51,132.84,132.53,130.18,130.13,129.25,128.16,127.72,118.56,116.18,114.72,112.29,110.62,85.02,48.36.ESI-HRMS:Calcd.for C₂₁H₁₄ClN₅O₂[M–H]^-402.0763,found:402.0757.

Example 27: preparation of N- [ 3-cyano-1- (2-hydroxy-2-methylpropyl) -1H-indol-5-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D23-5)

Preparation of 1- (2-hydroxy-2-methylpropyl) -5-nitro-1H-indole-3-carbonitrile (D23-3): the preparation method is the same as example 1 with oxidized isobutene as the raw material, 1.5g of yellow solid is obtained, and the yield is as follows: 57.9 percent. M.p 156.2.2-157.8 ℃.¹H NMR(400MHz,DMSO-d₆)δ8.48(s,1H),8.43(d,J＝1.3Hz,1H),8.17(dd,J＝9.2,2.0Hz,1H),8.00(d,J＝9.2Hz,1H),4.85(s,1H),4.28(s,2H),1.12(s,6H).MS:m/z 260.1[M+H]⁺.

1- (2-hydroxy-2-methylpropyl) -5-amino-1H-indolesPreparation of 3-carbonitrile (D23-4) hydrochloride: the preparation method is the same as example 1 with D23-3 as the raw material, 2.1g of white solid is obtained, and the yield is as follows: 79.2 percent. M.p 245.1.1-246.8 ℃,¹H NMR(400MHz,DMSO-d₆)δ10.38(s,3H),8.28(s,1H),7.89(d,J＝8.9Hz,1H),7.65(d,J＝2.0Hz,1H),7.30(dd,J＝8.9,2.0Hz,1H),4.21(s,3H),1.09(s,6H).MS:m/z 230.1[M+H]⁺.

n- [ 3-cyano-1- (2-hydroxy-2-methylpropyl) -1H-indol-5-yl]-preparation of 6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D23-5): the preparation method is the same as example 1 with D23-4 hydrochloride as the raw material, 0.38g is obtained, and the yield is as follows: 43.2 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ12.98(s,1H),10.50(s,1H),8.37(s,1H),8.30(d,J＝1.9Hz,1H),8.14(s,1H),7.74(d,J＝9.0Hz,1H),7.69(dd,J＝9.0,2.0Hz,1H),6.96(s,1H),4.77(s,1H),4.16(s,2H),1.10(s,6H).¹³C NMR(101MHz,DMSO-d₆)δ162.08,161.32,155.04,150.77,139.11,134.06,132.95,127.18,117.96,116.55,114.64,113.20,110.13,83.88,70.31,57.17,27.59.ESI-HRMS:Calcd.for C₁₈H₁₇N₅O₃[M–H]^-350.1259,found:350.1254.

Example 28: preparation of N- (3-cyano-1-isopropyl-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (D3-5)

Preparation of 1-cyclopentyl-6-nitro-1H-indole-3-carbonitrile (L3-3): the preparation method is the same as example 4 with bromo-cyclopentane and 6-nitro-1H-indole-3-carbonitrile (L-2) as raw materials to obtain 2.0g of yellow solid with the yield: 78.4 percent. M.p 175.1.1-176.5 ℃,¹H NMR(400MHz,DMSO-d₆)δ8.80(s,1H),8.74(d,J＝2.0Hz,1H),8.11(dd,J＝8.8,2.1Hz,1H),7.84(d,J＝8.8Hz,1H),5.22(p,J＝6.9Hz,1H),2.31-2.12(m,2H),1.97-1.63(m,7H).MS:m/z 256.1[M+H]⁺.

preparation of 1-cyclopentyl-6-amino-1H-indole-3-carbonitrile (L3-4) hydrochloride: the preparation method is the same as example 4 with L3-3 as the raw material, 2.1g white solid is obtained, yield: 80.5 percent. M.p 255.6, 255.6 to 256.8 ℃,¹H NMR(400MHz,DMSO-d₆)δ10.59(s,3H),8.51(s,1H),7.81(d,J＝1.8Hz,1H),7.76(d,J＝8.4Hz,1H),7.33(dd,J＝8.4,1.8Hz,1H),4.92(p,J＝7.1Hz,1H),2.28-2.13(m,2H),1.96-1.66(m,6H).MS:m/z 226.1[M+H]⁺.

preparation of N- (3-cyano-1-cyclopentyl-1H-indol-6-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (L3-5): the preparation method is the same as example 4 with L3-4 hydrochloride as the raw material, 0.43g yellow solid is obtained, yield: 49.2 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ13.01(s,1H),10.55(s,1H),8.38(d,J＝1.3Hz,2H),8.36(s,1H),7.72(dd,J＝8.7,1.7Hz,1H),7.61(d,J＝8.6Hz,1H),6.98(d,J＝0.9Hz,1H),4.86(p,J＝7.0Hz,1H),2.31-2.12(m,2H),2.01-1.63(m,6H).¹³C NMR(101MHz,DMSO-d₆)δ162.06,161.36,154.87,150.78,135.60,135.19,134.54,124.58,119.29,116.65,116.52,114.69,103.94,84.20,58.13,32.22,23.88.ESI-HRMS:Calcd.for C₁₉H₁₇N₅O₂[M–H]^-346.1309,found:346.1306.

Example 29: preparation of N- [ 3-cyano-1- (cyclopropylmethyl) -1H-indol-6-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (L4-5)

Preparation of 1- (cyclopropylmethyl) -6-nitro-1H-indole-3-carbonitrile (L4-3): the preparation method is the same as example 4 with bromomethylcyclopropane and 6-nitro-1H-indole-3-carbonitrile (L-2) as raw materials to obtain 2.2g of yellow solid with the yield: 77.7 percent. M.p157.2-158.6 ℃,¹H NMR(400MHz,DMSO-d₆)δ8.75-8.70(m,1H),8.12(dd,J＝8.8,2.1Hz,1H),7.86(d,J＝8.9Hz,1H),4.31(d,J＝7.3Hz,1H),1.10-1.30(m,1H),0.77-0.17(m,2H).MS:m/z 242.1[M+H]⁺.

preparation of 1- (cyclopropylmethyl) -6-amino-1H-indole-3-carbonitrile (L4-4) hydrochloride: the preparation method is the same as example 4 with L4-3 as the raw material, 1.8g white solid is obtained, yield: 72.9 percent. M.p 251.3-252.6 ℃ of the total weight of the mixture,¹H NMR(400MHz,DMSO-d₆)δ10.62(s,3H),8.50(s,1H),7.81(d,J＝1.8Hz,1H),7.76(d,J＝8.4Hz,1H),7.34(dd,J＝8.4,1.8Hz,1H),4.14(d,J＝7.1Hz,2H),1.32-1.22(m,2H),0.64-0.38(m,4H).MS:m/z 212.1[M+H]⁺.

n- [ 3-cyano-1- (cyclopropylmethyl) -1H-indol-6-yl]-preparation of 6-oxo-1, 6-dihydropyrimidine-4-carboxamide (L4-5): the preparation method is the same as example 4 with L4-4 hydrochloride as the raw material, 0.34g yellow solid is obtained, yield: 40.8 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ12.99(s,1H),10.51(s,1H),8.36(s,1H),8.34(d,J＝1.7Hz,1H),8.30(s,1H),7.70(dd,J＝8.7,1.8Hz,1H),7.60(d,J＝8.6Hz,1H),6.97(s,1H),4.06(d,J＝7.1Hz,2H),1.31-1.26(m,1H),0.74-0.12(m,4H).¹³C NMR(101MHz,DMSO-d₆)δ162.06,161.32,154.82,150.75,137.44,135.60,134.62,124.38,119.26,116.53,116.44,114.69,103.60,83.97,51.18,11.51,4.25.ESI-HRMS:Calcd.for C₁₈H₁₅N₅O₂[M–H]^-332.1153,found:332.1142.

Example 30: preparation of N- [ 3-cyano-1- (3-methylbut-2-en-1-yl) -1H-indol-6-yl ] -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (L5-5)

Preparation of 1- (3-methylbut-2-en-1-yl) -6-nitro-1H-indole-3-carbonitrile (L5-3): the preparation method of isoamylene bromide and 6-nitro-1H-indole-3-carbonitrile (L-2) serving as raw materials is the same as that of example 4, 1.9g of yellow solid is obtained, and the yield is as follows: 74.5 percent. M.p168.1-169.2 ℃,¹H NMR(400MHz,DMSO-d6)δ8.71–8.49(m,2H),8.12(dt,J＝8.7,1.5Hz,1H),7.86(d,J＝8.8Hz,1H),5.42(t,J＝7.1Hz,1H),5.03(d,J＝7.1Hz,2H),1.87(s,3H),1.76(s,3H).MS:m/z 256.1[M+H]⁺.

preparation of 1- (3-methylbut-2-en-1-yl) -6-amino-1H-indole-3-carbonitrile (L5-4) hydrochloride: the preparation method is the same as example 4 with L5-3 as the raw material, 1.6g white solid is obtained, yield: 61.5 percent. M.p 248.1.1-249.9 deg.c,¹H NMR(400MHz,DMSO-d₆)δ10.56(s,3H),8.39(s,1H),7.75(d,J＝8.5Hz,1H),7.63(d,J＝1.8Hz,1H),7.30(dd,J＝8.4,1.8Hz,1H),5.31(t,J＝7.1Hz,1H),4.87(d,J＝7.0Hz,2H),1.86(s,3H),1.74(s,3H).MS:m/z 226.1[M+H]⁺

n- [ 3-cyano-1- (3-methylbut-2-en-1-yl) -1H-indol-6-yl]-6-Preparation of oxo-1, 6-dihydropyrimidine-4-carboxamide (L5-5): the preparation method is the same as example 4 with L5-4 hydrochloride as the raw material, 0.75g yellow solid is obtained, yield: 86.4 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ13.00(s,1H),10.53(s,1H),8.37(s,1H),8.31(d,J＝1.7Hz,1H),8.23(s,1H),7.66(dd,J＝8.6,1.8Hz,1H),7.60(d,J＝8.6Hz,1H),6.97(s,1H),5.45-5.27(m,1H),4.81(d,J＝7.0Hz,2H),1.86(s,3H),1.73(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ162.04,161.36,154.90,150.78,137.89,137.31,135.41,134.62,124.50,119.29,119.17,116.61,116.39,114.69,103.54,83.95,45.03,25.82,18.43.ESI-HRMS:Calcd.for C₁₉H₁₇N₅O₂[M–H]^-346.1309,found:346.1352.

Example 31: preparation of N- (3-cyano-1-allyl-1H-indol-6-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (L6-5)

Preparation of 1-allyl-6-nitro-1H-indole-3-carbonitrile (L6-3): the preparation method of bromopropene and 6-nitro-1H-indole-3-carbonitrile (L-2) as raw materials is the same as in example 4, and 2.0g of yellow solid is obtained, with the yield: 88.1 percent. M.p 1145.2-147.0 ℃ of the total weight of the mixture,¹H NMR(400MHz,DMSO-d₆)δ8.65-8.64(m,2H),8.11(dd,J＝8.8,2.0Hz,1H),7.87(d,J＝8.8Hz,1H),6.12-6.02(m,1H),5.26(dd,J＝10.3,1.4Hz,1H),5.19-4.99(m,3H).MS:m/z 228.1[M+H]⁺.

preparation of 1-allyl-6-amino-1H-indole-3-carbonitrile (L6-4): the preparation method was the same as example 4 using 1-allyl-6-nitro-1H-indole-3-carbonitrile (L6-3) as a starting material to give 1.5g of a white solid with the yield: and (4) 64.4%. M.p 245.1.1-246.6 ℃,¹H NMR(400MHz,DMSO-d₆)δ10.58(s,3H),8.41(s,1H),7.77(d,J＝8.5Hz,1H),7.68(d,J＝1.8Hz,1H),7.33(dd,J＝8.5,1.8Hz,1H),6.08-5.98(m,1H),5.25(dd,J＝10.3,1.4Hz,1H),5.09(dd,J＝17.1,1.5Hz,1H),4.95(d,J＝5.6Hz,2H).MS:m/z 198.0[M+H]⁺

preparation of N- (3-cyano-1-allyl-1H-indol-6-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide (L6-5): with 1-allyl-6-amino-1H-indole-3-carbonitrile (L6-4) as a starting material, prepared in the same manner as in example 4 to give 0.45g of a yellow solid in yield: 56.4 percent. M.p>290℃，¹H NMR(400MHz,DMSO-d₆)δ13.01(s,1H),10.51(s,1H),8.38(s,1H),8.29(d,J＝1.7Hz,1H),8.26(s,1H),7.71(dd,J＝8.7,1.8Hz,1H),7.63(d,J＝8.6Hz,1H),6.98(d,J＝1.0Hz,1H),6.10-6.01(m,1H),5.25(dd,J＝10.3,1.5Hz,1H),5.10(dd,J＝17.1,1.6Hz,1H),4.89(d,J＝5.6Hz,2H).¹³C NMR(101MHz,DMSO-d₆)δ162.06,161.31,154.80,150.74,137.74,135.58,134.72,133.35,124.36,119.34,118.33,116.64,116.28,114.69,103.62,84.34,49.32.ESI-HRMS:Calcd.for C₁₇H₁₃N₅O₂[M–H]^-318.0996,found:318.1011.

Test example 1: examination of xanthine oxidase inhibitory Activity of the Compound produced in the above example

1. Test materials

1.1 reagent: xanthine oxidase (Sigma, USA), xanthine (98.0%, carbofuran), sodium pyrophosphate (99.0%, Body chemical Co., Ltd. of Tianjin), disodium edetate (99.0%, Body chemical Co., Ltd. of Tianjin)

1.2 Instrument: electronic analytical balance (AR1140 type), electric heating constant temperature water bath (DK-98-1 type), enzyme mark instrument (Synergy H1 type)

1.3 test samples: positive allopurinol, compound prepared from the same

2. Test method

2.1 preparation method

Preparing a buffer solution: 0.1mol/L sodium pyrophosphate 0.3mmol/L EDTA disodium salt, pH value 8.3

Compound solution preparation: the corresponding compounds were first prepared as 10mM DMSO solutions and then diluted with buffer to the desired concentration for testing

Preparing a xanthine solution: 30.42mg of xanthine is precisely weighed and placed in a 100mL measuring flask, 2mL of 1M sodium hydroxide solution is firstly added for dissolving, and then buffer solution is added for diluting to a scale mark, so as to obtain mother liquor with the concentration of 2000 mu M. Diluting with buffer solution according to requirement, and testing in vitro activity to obtain xanthine solution with concentration of 500 μ M

2.2 enzyme Activity detection method

To a 96-well plate, 40. mu.L of a xanthine oxidase solution and 100. mu.L of an inhibitor solution were sequentially added, and 50. mu.L of the xanthine solution was added after incubation at 25 ℃ for 15min (since the reaction was started by addition of xanthine, the addition of xanthine was quickly and immediately performed to prevent the decrease in the reaction rate), and then absorbance was measured at 295nm every 60 seconds. The blank group used the corresponding drug solvent as a control.

(a2-a1)/T inhibition ratio (V)_{Blank space}-v_Testing)/v_{Blank space}×100％

Wherein A1 represents the absorbance of the reaction solution detected by the instrument at time T1; a2 represents the absorbance of the reaction solution detected by the instrument at time T2; t represents the time interval between two readings, which can be expressed by the formula T-T2-T1; v represents the rate of reaction: v_{Blank space}Indicating the reaction rate of the reaction solution without adding xanthine oxidase inhibitor; v_TestingThe reaction rate of the reaction solution when the xanthine oxidase inhibitor was added was shown.

IC was performed on compounds with inhibition greater than 50% using 10. mu.M as the primary screen concentration₅₀And (6) testing.

2.2 statistical methods

All data were examined using the SPSS (17.0) statistical software package. Results are expressed as mean ± sd, comparisons of mean between groups for homogeneity of variance analysis, and Dunnett's test analysis for comparison between groups

3. The experimental results are as follows:

the experimental results show that the prepared target compounds all show stronger xanthine oxidase inhibition activity (the experimental data are shown in table 1).

TABLE 1 Effect of the prepared compounds on xanthine oxidase Activity (M + -SD)

As can be seen from the data in Table 1, most of the compounds provided by the present invention exhibited significant xanthine oxidase inhibitory activity, IC₅₀The value is between 0.08 and 1.72 mu M. The compounds have good in-depth research value as xanthine oxidase inhibitors.

Test example 2: evaluation of uric acid-lowering Activity of Compound D10-5 prepared in the above example in rat model for acute hyperuricemia

1. Laboratory animal and main reagent

Male SD rats 60 (ethical Committee approval No.: 180-; 220g (6 weeks old)), were used after one week of acclimation (purchased from animal laboratories, university of Shenyang pharmacy).

The main reagents are as follows: allopurinol (Annagi chemical reagent, Inc.), Potassium Oxonate (Annagi chemical reagent, Inc.), Uric Acid (UA) kit (Nanjing Biotech, Inc.)

2. Experimental methods

2.1 animal groups: after one week of adaptive feeding of 100 SPF-grade SD rats with 180-220g, the rats were randomly divided into a model group, a positive control group (allopurinol) and a compound D10-5(10mg/Kg) group, and each group had 8 rats. Another 8 blank groups were taken.

2.2, a molding method:

potassium Oxonate (300mg/kg) was administered by intraperitoneal injection.

2.3 administration mode:

1h after the potassium oxonate is administered, the drug (0.5% CMC-Na solution is made into a uniform suspension) is administered by intragastric administration.

3. Detecting the index

Blood was collected from the

orbit

1,2,3,5,8 hours after administration, and after standing in a 1.5ml EP tube for 2 hours, at 4 ℃ 3000r/min, centrifuged for 10min to obtain serum, and the concentration of uric acid in serum was measured using a Uric Acid (UA) kit according to the instructions.

4. Results of the experiment

The experimental results are shown in fig. 1.

The uric acid reducing activity of the compound D10-5 is evaluated by adopting a potassium oxonate-induced acute hyperuricemia rat model. With 10mg/kg oral dose and allopurinol (10mg/kg) as the positive control, 1h serum uric acid level was reduced by 43.7% (P <0.0001) and AUC (1-8h) was reduced by 24.0% (P <0.0001) compared to the model group. The result shows that the compound D10-5 can obviously reduce the serum uric acid level and is a promising lead compound for treating hyperuricemia. Compound D10-5 can significantly reduce rat serum uric acid levels in a rat model of acute hyperuricemia.

Formulation example 1: using the Compound D1-5 prepared in example 1, tablets were prepared

Prescription composition and content

The prescription of the coating liquid is as follows:

opadry (03B28796) 21g

Proper amount of 95% ethanol

Made into about 430mL

Process for the preparation of a coating

Mixing the auxiliary materials which are sieved by a 100-mesh sieve and the compound of the invention which are sieved by a 60-mesh sieve, preparing soft materials by 95% ethanol, granulating by a 18-mesh sieve, ventilating and drying at 60 ℃, granulating by a 16-mesh sieve, uniformly mixing with magnesium stearate, and punching into tablets by a shallow concave punch with phi 6 mm.

Preparing a coating solution: adding a proper amount of 95% ethanol into a proper container, starting a stirrer, uniformly adding the Opadry (03B28796) solid powder of the prescription amount into the vortex, simultaneously avoiding the powder from floating on the liquid surface as much as possible, if necessary, increasing the rotating speed to keep the proper vortex, reducing the stirring speed after all the Opadry (03B28796) is added, eliminating the vortex, and continuously stirring for 45min to obtain the product.

Preparation of film-coated tablets: placing the tablet core in a coating pan, keeping the temperature at 60 + -5 deg.C, and coating.

Claims

1. An N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative or a pharmaceutically acceptable salt or isomer thereof, characterized in that the N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative has the following general formula:

2. The N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative or a pharmaceutically acceptable salt, isomer thereof as claimed in claim 1, characterized in that the N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative is any of the following compounds:

d1-5: n- (3-cyano-1H-indol-5-yl) -6-oxo-1, 6-dihydropyrimidine-4-carboxamide

3. A process for the preparation of N-indole-1, 6-dihydropyrimidine-4-carboxamide derivatives as claimed in claim 1 or 2, characterized in that it comprises the following steps:

5/6-nitro-1H-indole (D-0 or L-0) is taken as a starting material, Vilsmeier-Haack reaction and cyanidation reaction are sequentially carried out to obtain a common intermediate 5/6-nitro-1H-indole-3-carbonitrile (D-2 or L-2), 5/6-nitro-1H-indole-3-carbonitrile reacts with different halogenated hydrocarbons to obtain a corresponding intermediate Dx-3 or Lx-3, then Dx-3 or Lx-3 is reduced into corresponding intermediate Dx-4 or Lx-4 by zinc powder, and finally, carrying out amide condensation on Dx-4 or Lx-4 and 6-oxo-1, 6-dihydropyrimidine-4-formic acid to obtain a compound shown in a general formula I;

4. a pharmaceutical composition comprising one or more of the N-indole-1, 6-dihydropyrimidine-4-carboxamide derivatives of claim 1 or 2, or a pharmaceutically acceptable salt, isomer thereof; also comprises one or the combination of pharmaceutically acceptable auxiliary materials, carriers and diluents; wherein the route of administration of the pharmaceutical composition comprises: oral, nasal, transdermal, pulmonary and parenteral administration; the dosage form of the pharmaceutical composition comprises: tablets, capsules, lozenges, syrups, emulsions, injections, aerosols and dragees; the weight percentage of the N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative or the pharmaceutically acceptable salt and isomer thereof in the pharmaceutical composition is 0.5-20%.

5. The use of an N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative according to claim 1 or 2, or of a pharmaceutically acceptable salt, isomer thereof, for the preparation of a medicament for the treatment and/or prevention of hyperuricemia.

6. The use of the N-indole-1, 6-dihydropyrimidine-4-carboxamide derivative according to claim 1 or 2, or of a pharmaceutically acceptable salt or isomer thereof, for the preparation of a medicament for the treatment and/or prophylaxis of gout.