CN111662299A

CN111662299A - Substituted indolyazepinone compound and preparation method and application thereof

Info

Publication number: CN111662299A
Application number: CN202010660872.6A
Authority: CN
Inventors: 罗海彬; 吴德燕; 姜赞; 黄仪有; 周倩; 黄雅丹
Original assignee: National Sun Yat Sen University
Current assignee: National Sun Yat Sen University
Priority date: 2020-07-10
Filing date: 2020-07-10
Publication date: 2020-09-15
Anticipated expiration: 2040-07-10
Also published as: CN111662299B

Abstract

The invention discloses a substituted indolyazepinone compound or pharmaceutically acceptable salt thereof, and a preparation method and application thereof. The structure of the compound is shown as (I). The substituted benzazepine compound has a novel structure, and shows excellent inhibition effect on phosphodiesterase type 5, namely the compound can be used as a compoundThe phosphodiesterase type 5 inhibitor is used for preparing a medicament for treating and/or preventing related diseases caused by the phosphodiesterase type 5, such as male sexual dysfunction, pulmonary hypertension, pulmonary fibrosis, organ fibrosis, tumor resistance and the like. The invention also provides a synthesis method of the substituted indole-aza-ketone compound, which adopts nitroolefin and halogenated hydrocarbon as starting materials to obtain a final product through reactions such as reduction, cyclization, alkylation, rearrangement and the like. The synthetic method has the advantages of cheap and easily-obtained raw materials, low toxicity, mild reaction conditions, safe operation, simple synthetic steps and the like.

Description

Substituted indolyazepinone compound and preparation method and application thereof

Technical Field

The invention relates to the technical field of medicinal chemistry, in particular to a substituted indolyazepinone compound and a preparation method and application thereof.

Background

Cyclic nucleotide Phosphodiesterases (PDEs) are an important super enzyme family, which effectively control the intracellular concentrations of cAMP and cGMP by hydrolyzing cAMP and cGMP, thereby regulating the biochemical effects conducted by second messengers in vivo. PDEs (PDE1-PDE11) are widely distributed in mammalian tissues, and the diversity of PDEs enables different PDE enzymes to have specific distribution at cellular and subcellular levels, can selectively regulate various cellular functions, and are good drug design and treatment targets.

Phosphodiesterase type 5 (PDE5), a family of PDEs specific for cGMP, was first isolated and identified in mouse platelets and later found and purified in mouse lungs. Human PDE5A is mainly distributed in aortic vascular smooth muscle cells, heart, placenta, skeletal muscle cells, pancreas, platelets, and also has a very small distribution in brain, liver, and lung. The level of PDE5 in the corpus cavernosum of the male penis is much higher than in other PDE families.

PDE5A inhibitors are one of the most successful in developing inhibitors of PDEs. Sildenafil (vildenafil, Viagra), Tadalafil (Tadalafil, Cialis), Vardenafil (Vardenafil, Levitra), Avanafil (Avanafil, Stendra) are drugs for treating erectile dysfunction, and Sildenafil and Tadalafil are later approved as novel targeted anti-PAH drugs in 2005 and 2009, respectively. In addition, PDE5 inhibitors have been found to be useful in improving memory, anti-tumor, treating pulmonary diseases, treating cardiac diseases, and the like. Nevertheless, the existing PDE5A inhibitors have considerable side effects: such as headache, blurred vision, blush, congestion of nasal mucosa, digestive dysfunction, and muscle pain. On the other hand, the existing medicines can cause more serious adverse reactions to patients with serious liver and kidney insufficiency. Therefore, the development of a new generation of selective PDE5 inhibitor with strong curative effect and small side effect has important social and economic significance.

Disclosure of Invention

The invention aims to provide a substituted indolyazalone compound. The compound has a novel structure, shows excellent inhibition effect on phosphodiesterase type 5, can be used as a phosphodiesterase type 5 inhibitor, and can be further prepared into a medicament for treating and/or preventing diseases related to the phosphodiesterase type 5, such as male sexual dysfunction, pulmonary hypertension, pulmonary fibrosis, organ fibrosis, tumor resistance and the like.

The invention also aims to provide a preparation method of the substituted benzazepine compound.

The invention further aims to provide application of the substituted benzazepine compound.

The above object of the present invention is achieved by the following scheme:

a substituted benzazepine compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof:

wherein R is₁Selected from hydrogen, C_1-6Substituted or unsubstituted alkanes, C_1-6Substituted or unsubstituted cycloalkane;

R₂selected from substituted or unsubstituted benzyl, C_1-6Substituted or unsubstituted alkanes, C_1-6Substituted or unsubstituted cycloalkane;

R₃selected from hydrogen, deuterium, halogen, hydroxyl, sulfydryl, carboxyl, sulfonic acid group, methylsulfonyl, C_1-3Substituted or unsubstituted alkoxy;

wherein said C_1-6Substituted or unsubstituted alkanes, C_1-6Substituted or unsubstituted cycloalkane, C_1-3The substituent in the substituted or unsubstituted alkoxy group is C_1-3Alkoxy radical, C_1-3Etheralkyl radical, C_1-3Carboxylic acid, C_1-3Carboxylic acid ester, C_1-3Amino or C_1-3An amide group;

the substituent in the substituted or unsubstituted benzyl is halogen or C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy or C_1-3One or more of haloalkoxy.

Preferably, said R is₁Selected from hydrogen, C_1-6Alkane, C_1-6Ethereal hydrocarbyl radical, C_1-6Alkylamino radical, C_1-5Carboxylic acid, C_1-5Carboxylic acid ester, C_1-5An alkylamide group;

the R is₂Is selected from substituted or unsubstituted benzyl, wherein the substituent is one or more of halogen, methyl, ethyl, methoxy and ethoxy;

the R is₃Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, carboxyl, methoxy, ethoxy, fluoromethoxy, fluoroethoxy, chloromethoxy or chloroethoxy.

Preferably, said R is₁Selected from hydrogen,

Preferably, said R is₂Is selected from

The R is₃Selected from hydrogen, fluoro, hydroxy, methoxy or difluoromethoxy.

Preferably, the substituted indolocazalone compound has a structure shown in one of the following formulas:

preferably, the pharmaceutically acceptable salt of the substituted benzazolazedone compound is a product obtained by reacting the compound of the formula (I) with acid.

Preferably, the acid is hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, hydrofluoric acid, hydrobromic acid, acetic acid, oxalic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, succinic acid, malic acid, or glutamic acid.

The invention also discloses a preparation method of the substituted indole-aza-ketone compound, when R is₃To remove C_2-3When the substituent or the non-substituent alkoxy is other than the substituent or the non-substituent alkoxy, the method comprises the following steps:

s1, mixing a compound 1 with a reducing agent in a solvent at the temperature of-30-40 ℃, and reacting at-30-40 ℃ to obtain a compound 2;

s2, mixing the compound 2 with a reducing agent in a solvent, and reacting at 0-60 ℃ under the action of hydrogen to obtain a compound 3;

s3, mixing the compound 3 with an alkaline substance in a solvent at the temperature of-30-40 ℃, reacting for 0-2 hours, adding halogenated hydrocarbon, gradually heating to 25-100 ℃, and reacting to obtain a compound 4;

s4, mixing the compound 4 with an alkaline substance in a solvent at the temperature of-30-40 ℃, reacting for 0-2 hours, adding halogenated hydrocarbon, gradually heating to 25-100 ℃, and reacting to obtain a compound 5;

s5, mixing the compound 5 with an acidic substance, and heating to 25-120 ℃ for reaction to obtain a compound shown in the formula (I);

when R is₃Is C_2-3When the alkoxy is substituted or unsubstituted, the method comprises the following steps:

s11, mixing the compound 1 'with a reducing agent in a solvent at the temperature of-30-40 ℃, and reacting at the temperature of-30-40 ℃ to obtain a compound 2';

s21, mixing the compound 2 'with a reducing agent in a solvent, and reacting at 0-60 ℃ under the action of hydrogen to obtain a compound 3';

s31, mixing the compound 3 'with an alkaline substance in a solvent at the temperature of-30-40 ℃, reacting for 0-2 hours, adding halogenated hydrocarbon, gradually heating to 25-100 ℃, and reacting to obtain a compound 4';

s41, mixing the compound 4 'with an alkaline substance in a solvent at the temperature of-30-40 ℃, reacting for 0-2 hours, adding halogenated hydrocarbon, gradually heating to 25-100 ℃, and reacting to obtain a compound 5';

s51, mixing the compound 5 'with an acidic substance, and heating to 25-120 ℃ for reaction to obtain a compound 6';

s61, mixing the compound 6' with an alkaline substance in a solvent at the temperature of-30-40 ℃, reacting for 0-2 hours, adding an alkylating reagent, gradually heating to 25-100 ℃, and reacting to obtain a compound shown in the formula (I);

wherein R is⁴Is isopropyl, benzhydryl, dialkyl methyl or diaryl methyl, and the alkyl in the dialkyl methyl is C_1-5The aryl in the diarylmethyl is substituted or unsubstituted phenyl.

Preferably, in the above steps S1 to S5, the solvent in S11 to S61 is one or more of tetrahydrofuran, methanol, ethanol, propanol, isopropanol, acetonitrile, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, hexamethyl phosphoramide, N-methylpyrrolidone, dichloromethane, chloroform, dichloroethane, diethyl ether, ethyl acetate, 1, 4-dioxane, benzene, toluene, or xylene.

Preferably, the reducing agent in steps S1 and S11 is one or more of sodium borohydride, lithium borohydride, potassium borohydride, sodium triacetoxyborohydride, or sodium cyanoborohydride.

More preferably, the reaction temperature in the steps S1 and S11 is-10 to 10 ℃; the reducing agent in steps S1 and S11 is one or more selected from sodium borohydride, lithium borohydride and potassium borohydride; the reaction is carried out in one or more solvents selected from methanol, ethanol, propanol or tetrahydrofuran.

Preferably, the reducing agent in steps S2 and S21 is one or more of palladium, palladium on carbon, palladium hydroxide, platinum on carbon, platinum dioxide or nickel.

More preferably, the reaction temperature in the steps S2 and S21 is 35-55 ℃; the reducing agent in the steps S2 and S21 is one or more selected from palladium carbon, palladium hydroxide, platinum carbon, platinum dioxide and nickel; the reaction is carried out in one or more solvents selected from methanol, ethanol, propanol or tetrahydrofuran.

Preferably, the basic substance in steps S3, S4, S31, S41 and S61 is one or more of sodium hydroxide, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, potassium tert-butoxide, sodium hydride, lithium bistrimethylsilyl amide, sodium bistrimethylsilyl amide, potassium bistrimethylsilyl amide or lithium diisopropylamide, respectively.

Preferably, the initial temperature in the steps S3 and S31 is-10 to 10 ℃, and the reaction temperature is 15 to 35 ℃; the alkaline substance in the steps S3 and S31 is one or more selected from potassium tert-butoxide, sodium hydride, potassium hydride, lithium bis (trisilyl) amide, sodium bis (trisilyl) amide and potassium bis (trisilyl) amide; the reaction is carried out in one or more solvents selected from dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethyl phosphoramide, N-methyl pyrrolidone, or tetrahydrofuran.

Preferably, the initial temperature in the steps S4 and S41 is-10 to 10 ℃, and the reaction temperature is 25 to 45 ℃; the alkaline substance in the steps S4 and S41 is one or more selected from potassium tert-butoxide, sodium hydride, potassium hydride, lithium bis (trisilyl) amide, sodium bis (trisilyl) amide and potassium bis (trisilyl) amide; the reaction is carried out in one or more solvents of dimethylformamide, dimethylacetamide, dimethyl sulfoxide, hexamethyl phosphonic triamide, N-methyl pyrrolidone and tetrahydrofuran.

Preferably, the acidic substance in steps S5 and S51 is one or more of polyphosphoric acid, aluminum trichloride, concentrated sulfuric acid, or acetic anhydride.

Preferably, the reaction temperature in the step S5S51 is 50-100 ℃; the acidic substance in the step S5S51 is one or more selected from polyphosphoric acid and aluminum trichloride; the reaction is carried out in the absence of solvent or one or more solvents of toluene and xylene.

Preferably, the initial temperature in the step S61 is-10 to 10 ℃, and the reaction temperature is 15 to 35 ℃; the alkaline substance in the step S61 is selected from one or more of sodium hydroxide, potassium tert-butoxide, sodium hydride, potassium hydride, lithium bis-trisilyl amide, sodium bis-trisilyl amide, and potassium bis-trisilyl amide; the reaction is carried out in one or more solvents selected from dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethyl phosphoramide, N-methyl pyrrolidone, or tetrahydrofuran.

The application of the substituted indole nitrogen heterocyclic ketone compound or the pharmaceutically acceptable salt thereof as a phosphodiesterase type 5 inhibitor is also in the protection scope of the invention.

The application of the substituted indole nitrogen heterocyclic ketone compound or the pharmaceutically acceptable salt thereof in preparing the medicament for treating diseases related to phosphodiesterase type 5 is also within the protection scope of the invention.

Preferably, the medicament is in the form of oral tablets, pills, capsules, injection, powder injection, percutaneous or subcutaneous absorbents.

Preferably, the diseases related to phosphodiesterase type 5 are male sexual dysfunction, pulmonary hypertension, pulmonary fibrosis, organ fibrosis and/or tumor drug resistance.

Compared with the prior art, the invention has the following beneficial effects:

the substituted indolizine nitrogen heterocyclic ketone compound has a novel structure, shows excellent inhibiting effect on phosphodiesterase type 5, namely can be used as a phosphodiesterase type 5 inhibitor to prepare medicaments for treating and/or preventing related diseases caused by the phosphodiesterase type 5, such as male sexual dysfunction, pulmonary hypertension, pulmonary fibrosis, organ fibrosis, tumor resistance and other diseases.

The invention also provides a synthesis method of the substituted indole-aza-ketone compound, which adopts nitroolefin and halogenated hydrocarbon as starting materials to obtain a final product through reactions such as reduction, cyclization, alkylation, rearrangement and the like. The synthetic method has the advantages of cheap and easily-obtained raw materials, low toxicity, mild reaction conditions, safe operation, simple synthetic steps and the like.

Drawings

FIG. 1 shows the in vivo efficacy of compound C21 in anti-pulmonary hypertension animals.

Detailed Description

The present invention is further described in detail below with reference to specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.

EXAMPLE 1 Synthesis of Compound C1

(1) Synthesis of intermediate M1

Sodium borohydride (57mg, 1.5mmol) was slowly added to a solution of methyl 7-fluoro-3- (2-nitrovinyl) -1H-indole-4-carboxylate (264mg,1.0mmol) in 10mL of anhydrous tetrahydrofuran under ice-bath, followed by slowly dropping 3.0mL of methanol for reaction for 1 hour under ice-bath conditions. After the reaction is finished, adding saturated ammonium chloride solution to quench the reaction, concentrating the system to remove most of organic solvent, extracting with ethyl acetate, and using anhydrous organic phaseDrying over sodium sulfate and column chromatography gave intermediate M1(165mg) as a white solid in 62% yield.¹H NMR(400MHz,CDCl₃)8.56(s,1H),7.84(dd,J＝8.4,5.2Hz,1H),7.25(d,J＝2.5Hz,1H),6.95(dd,J＝9.9,8.5Hz,1H),4.73(t,J＝6.5Hz,2H),3.96(s,3H),3.71(t,J＝6.5Hz,2H)。

(2) Synthesis of intermediate M2

Intermediate M1(266mg,1.0mmol) was dissolved in 10mL of methanol, Pd/C (30mg) was added, and the mixture was stirred under hydrogen at 45 ℃ overnight. After the reaction was completed, the system was filtered through celite, washed with methanol, and the filtrate was separated by column chromatography to obtain intermediate M2(118mg) as a white solid with a yield of 58%.¹H NMR(400MHz,DMSO)8.00(t,J＝5.0Hz,1H),7.65(dd,J＝8.3,4.9Hz,1H),7.32(s,1H),6.98(dd,J＝11.0,8.3Hz,1H),3.86(s,1H),3.08(dd,J＝12.5,6.3Hz,1H),2.92(s,2H),2.82(dd,J＝13.9,7.2Hz,1H)。

(3) Synthesis of intermediate M3

Under the protection of ice bath and dry tube, intermediate M2(102mg, 0.5mmol) was dissolved in N, N-dimethylformamide (3.0mL), sodium hydride (60% in mineral oil, 20mg, 0.5mmol) was slowly added to the system, after 30 minutes of reaction, 4-fluorobenzyl bromide (95mg in 1.0mL of N, N-dimethylformamide) was added, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, the reaction was quenched by pouring into ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain intermediate M3(133mg) as a white solid with a yield of 85%.¹H NMR(400MHz,CDCl₃)7.96(dd,J＝8.4,4.6Hz,1H),7.14(dd,J＝8.5,5.4Hz,2H),7.02(dd,J＝11.8,5.2Hz,2H),6.97(dd,J＝7.7,4.4Hz,2H),6.54(s,1H),5.44(s,2H),3.65–3.51(m,2H),3.08–3.01(m,2H)。

(4) Synthesis of the end product C1

Intermediate M3(156mg, 0.5mmol) was mixed well in polyphosphoric acid (5.0mL) and gradually warmed to 90 ℃ under argon for 3 hours. After the reaction is finished, pouring the system into an ice-water mixed solution, extracting with ethyl acetate, washing with water and saturated sodium chloride respectively, drying with anhydrous sodium sulfate, and separating by column chromatography to obtain a product C1(47mg) which is a white solid with the yield of 30%. Purity: 96 percent.¹H NMR(400MHz,Acetone-d₆)10.83(s,1H),7.84(dd,J＝8.3,4.9Hz,1H),7.47(s,1H),7.30(dd,J＝8.3,5.6Hz,2H),7.04(t,J＝8.8Hz,2H),6.95–6.85(m,1H),4.18(s,2H),3.60(s,2H),2.99(s,2H).¹³C NMR(126MHz,Acetone-d₆)169.65,161.48(d,J＝242.5Hz),151.06(d,J＝248.1Hz),136.07,135.18(d,J＝3.1Hz),130.16(d,J＝8.1Hz),124.14(d,J＝7.2Hz),123.36(d,J＝13.5Hz),120.74,120.33,115.07(d,J＝21.4Hz),113.01,105.89(d,J＝17.4Hz),42.32,30.96,27.41。

EXAMPLE 2 Synthesis of Compound C2

(1) Synthesis of intermediate M4

The procedure of example 1 was followed, substituting M2 for the starting material and reacting with 4-chlorobenzyl bromide, to give intermediate M4 as a white solid in 85% yield.¹H NMR(400MHz,DMSO-d₆)8.08(t,J＝5.7Hz,1H),7.68(dd,J＝8.4,4.7Hz,1H),7.50(s,1H),7.38(d,J＝8.4Hz,2H),7.15(d,J＝8.4Hz,2H),7.01(dd,J＝12.4,8.4Hz,1H),5.48(s,2H),3.40(dd,J＝9.6,5.4Hz,2H),2.93(s,2H)。

(2) Synthesis of the end product C2

The starting material was replaced by M4 and reacted in polyphosphoric acid according to the procedure of example 1 to give the final product C2 as a white solid in 40% yield. Purity: 97 percent.¹H NMR(400MHz,DMSO-d₆)11.69(s,1H),7.99(t,J＝5.4Hz,1H),7.65(dd,J＝8.3,4.8Hz,1H),7.34(d,J＝8.3Hz,2H),7.26(d,J＝8.3Hz,2H),6.96(dd,J＝10.7,8.5Hz,1H),4.07(s,2H),3.39(s,2H),2.85(s,2H).¹³C NMR(126MHz,DMSO-d₆)169.40,150.96(d,J＝247.7Hz),138.60,136.29,131.32,130.61(2C),129.89(2C),128.88,123.94(d,J＝6.7Hz),123.19(d,J＝13.4Hz),121.06,112.88,106.25(d,J＝17.1Hz),42.25,31.29,27.57.HRMS(ESI)m/z calcd C₁₈H₁₄N₂OFCl[M+H]⁺239.0851,found329.0858。

EXAMPLE 3 Synthesis of Compound C3

(1) Synthesis of intermediate M5

The procedure of example 1 was followed, substituting M2 for the starting material, and reacting with 3, 4-difluorobenzyl bromide to give intermediate M5 as a white solid in 85% yield.¹H NMR(400MHz,CDCl₃)7.97(dd,J＝8.4,4.6Hz,1H),7.12(dt,J＝10.0,8.3Hz,1H),7.03–6.91(m,3H),6.88(dd,J＝5.2,3.2Hz,1H),6.54(s,1H),5.42(s,2H),3.62(dd,J＝9.8,5.7Hz,2H),3.13–2.97(m,2H)。

(2) Synthesis of the end product C3

The starting material was replaced by M5 and reacted in polyphosphoric acid according to the procedure of example 1 to give the final product C3 as a white solid in 30% yield. Purity: 99 percent.¹H NMR(400MHz,CDCl₃)8.49(s,1H),7.93(dd,J＝8.0,4.8Hz,1H),7.09(dd,J＝18.2,8.4Hz,1H),7.03–6.92(m,2H),6.90(dd,J＝6.7,3.1Hz,1H),6.60(s,1H),4.07(s,2H),3.62(s,2H),2.96(s,2H)。

EXAMPLE 4 Synthesis of Compound C4

(1) Synthesis of intermediate M6

The starting material was replaced with 7-methoxy-3- (2-nitrovinyl) -1H-indole-4-carboxylic acid methyl ester and reacted with sodium borohydride to give intermediate M6 as a white solid in 60% yield according to the procedure of example 1.¹H NMR(400MHz,CDCl₃)8.54(s,1H),7.89(d,J＝8.3Hz,1H),7.16(d,J＝2.4Hz,1H),6.66(d,J＝8.4Hz,1H),4.73(t,J＝6.6Hz,2H),4.02(s,3H),3.94(s,3H),3.72(t,J＝6.6Hz,2H)。

(2) Synthesis of intermediate M7

The starting material was replaced by M6 and reacted under Pd/C, hydrogen conditions according to the procedure for example 1 to give intermediate M7 as a white solid in 60% yield.

(3) Synthesis of intermediate M8

The starting material was replaced by M7 and reacted with 4-fluorobenzyl bromide following the procedure of example 1 to give intermediate M8 as a white solid in 88% yield.¹H NMR(400MHz,CDCl₃)7.99(d,J＝8.3Hz,1H),7.08(dd,J＝8.4,5.5Hz,2H),6.99(t,J＝8.6Hz,2H),6.87(s,1H),6.74(d,J＝8.3Hz,1H),6.39(s,1H),5.56(s,2H),3.92(s,3H),3.59(d,J＝3.6Hz,2H),3.07–2.96(m,2H)。

(4) Synthesis of the end product C4

The starting material was replaced by M8 and reacted in polyphosphoric acid according to the procedure of example 1 to give the final product C4 as a white solid in 30% yield. Purity: 97 percent.¹H NMR(400MHz,CDCl₃)8.10(s,1H),7.98(d,J＝8.4Hz,1H),7.16(dd,J＝8.4,5.5Hz,2H),7.02(t,J＝8.6Hz,2H),6.73(d,J＝8.4Hz,1H),6.63(s,1H),4.08(s,2H),3.98(s,3H),3.63(dd,J＝9.7,5.6Hz,2H),3.03–2.95(m,2H).¹³C NMR(126MHz,DMSO-d₆)170.27,162.12,160.20,148.61,136.33(d,J＝2.9Hz),134.91,130.50(d,J＝8.0Hz),127.41,125.04,124.50,117.60,115.59,115.42,111.95,101.84,55.73,42.41,31.07,27.79.HRMS(ESI)m/z calcd C₁₉H₁₇N₂O₂F₂[M+H]^-323.1201,found 323.1201。

EXAMPLE 5 Synthesis of Compound C5

(1) Synthesis of intermediate M9

The procedure of example 1 was followed, substituting M7 for the starting material and reacting with 4-chlorobenzyl bromide, to give intermediate M9 as a white solid in 60% yield.¹H NMR(400MHz,CDCl₃)7.98(d,J＝8.4Hz,1H),7.27(d,J＝8.4Hz,2H),7.02(d,J＝8.4Hz,2H),6.87(s,1H),6.74(d,J＝8.3Hz,1H),6.41(s,1H),5.56(s,2H),3.90(s,3H),3.60(dd,J＝9.3,5.2Hz,2H),3.10–2.94(m,2H)。

(2) Synthesis of Compound C5

The starting material was replaced by M9 and reacted in polyphosphoric acid and the procedure of example 1 was followed to give compound C5 as a white solid in 51% yield. Purity: 95 percent.¹H NMR(500MHz,CDCl₃)8.27(s,1H),7.96(d,J＝8.3Hz,1H),7.26(d,J＝4.0Hz,2H),7.10(d,J＝8.3Hz,2H),6.70(d,J＝8.3Hz,1H),6.50(s,1H),4.05(s,2H),3.96(s,3H),3.60(s,2H),2.95(s,2H).¹³C NMR(126MHz,CDCl₃)171.60,148.56,136.65,132.62,132.52,129.82(2C),128.96(2C),127.33,125.82,125.21,116.65,113.11,102.10,55.50,43.05,31.76,27.52.HRMS(ESI)m/z calcd C₁₉H₁₇N₂O₂Cl₂[M+H]⁺341.1051,found 341.1047。

EXAMPLE 6 Synthesis of Compound C6

(1) Synthesis of intermediate M10

The starting material was replaced by M7 and reacted with 4-bromobenzyl bromide to give intermediate M10 as a white solid in 80% yield according to the procedure of example 1.

(2) Synthesis of Compound C6

The starting material was replaced by M10 and reacted in polyphosphoric acid according to the procedure of example 1 to give compound C6 as a white solid with a yield of 30%. Purity: 99 percent.¹H NMR(400MHz,CDCl₃)8.09(s,1H),7.97(d,J＝8.3Hz,1H),7.43(d,J＝8.3Hz,2H),7.05(d,J＝8.3Hz,2H),6.71(d,J＝8.4Hz,1H),6.28(s,1H),4.04(s,2H),3.96(s,3H),3.60(dd,J＝9.7,5.7Hz,2H),2.98–2.92(m,2H).¹³C NMR(126MHz,DMSO-d₆)170.26,148.62,139.61,134.41,131.68(2C),130.98(2C),127.38,125.07,124.53,119.54,117.62,112.14,101.89,55.74,42.40,31.27,27.77。

EXAMPLE 7 Synthesis of Compound C7

(1) Synthesis of intermediate M11

The procedure of example 1 was followed, substituting M7 for the starting material and reacting with 3-chlorobenzyl bromide, to give intermediate M11 as a white solid in 80% yield.

(2) Synthesis of Compound C7

The starting material was replaced by M11 and reacted in polyphosphoric acid according to the method of example 1 to give compound C7 as a white solid with 28% yield. Purity: 98 percent.¹³C NMR(126MHz,DMSO-d₆)170.22,148.63,142.69,134.20,133.40,130.74,128.58,127.50,127.32,126.50,125.10,124.56,117.64,112.23,101.95,55.75,42.41,31.49,27.78.。

EXAMPLE 8 Synthesis of Compound C8

(1) Synthesis of intermediate M12

The starting material was replaced by M7 and reacted with 3-chloro-4-methoxybenzyl bromide following the procedure of example 1 to give intermediate M11 as a white solid in 86% yield.¹H NMR(400MHz,CDCl₃)8.01(s,1H),7.96(d,J＝8.4Hz,1H),7.19(d,J＝2.1Hz,1H),6.94(dd,J＝8.5,2.1Hz,1H),6.94(dd,J＝8.5,2.1Hz,1H),6.84(d,J＝5.4Hz,2H),6.73(d,J＝8.4Hz,1H),6.40(s,1H),5.48(s,2H),3.93(s,3H),3.85(s,3H),3.56(dd,J＝9.7,5.6Hz,2H),3.03–2.98(m,2H)。

(2) Synthesis of Compound C8

The starting material was replaced by M12 and reacted in polyphosphoric acid according to the procedure of example 1 to give compound C8 as a white solid with a yield of 30%. Purity: 95 percent.¹H NMR(400MHz,CDCl₃)8.12(s,1H),7.97(d,J＝8.3Hz,1H),7.20(d,J＝2.0Hz,1H),7.02(dd,J＝8.3,1.9Hz,1H),6.86(d,J＝8.4Hz,1H),6.71(d,J＝8.3Hz,1H),6.41(s,1H),4.00(s,2H),3.96(s,3H),3.88(s,3H),3.61(s,2H),3.01–2.87(m,2H).¹³CNMR(126MHz,CDCl₃)171.76,153.82,148.58,132.92,131.37,130.18(2C),127.68(2C),127.41,125.71,125.22,122.64,116.67,112.91,112.33,102.02,56.21,55.49,43.07,31.23,27.5.HRMS(ESI)m/z calcd C₂₀H₁₉N₂O₃Cl[M+H]⁺371.1157,found 371.1144。

EXAMPLE 9 Synthesis of Compound C9

Compound C5(68mg, 0.2mmol) was dissolved in 0.5mL of dichloromethane, boron tribromide (100. mu.L) was added at room temperature, and the mixture was heated to 50 ℃ to react 4And (4) hours. After the reaction is finished, the reaction solution is poured into ice water to quench the reaction, ethyl acetate is used for extraction, saturated saline solution is used for washing, an organic phase is dried by anhydrous sodium sulfate, and a product C9(15mg) is obtained by column chromatography separation, brick red solid is obtained, and the yield is 23%.¹H NMR(400MHz,DMSO-d₆)10.99(s,1H),10.11(s,1H),7.63(t,J＝5.5Hz,1H),7.52(d,J＝8.1Hz,1H),7.34(d,J＝8.5Hz,2H),7.26(d,J＝8.5Hz,2H),6.54(d,J＝8.1Hz,1H),4.02(s,2H),2.81(s,2H)。

EXAMPLE 10 Synthesis of Compound C10

Compound C9(33mg, 0.1mmol) was dissolved in 3.0mL of a mixed solution of acetonitrile: water ═ 1:1, potassium hydroxide (56mg, 1.0mmol) was added under ice-bath, and after the system was clarified, diethyl bromofluoromethylphosphonate (0.5mmol) was added dropwise. The reaction was carried out at room temperature for 15 minutes. The reaction was quenched with ice water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and separated by column chromatography to give product C10(23mg) as a white solid in 60% yield. Purity: 99 percent.¹H NMR(400MHz,Acetone-d₆)10.66(s,1H),7.83(d,J＝8.3Hz,1H),7.34(d,2H),7.31(d,J＝4.5Hz,2H),7.28,7.15,6.97(t,1H),7.23(s,1H),7.00(d,J＝8.3Hz,1H),4.22(s,2H),3.65–3.56(m,2H),3.01(s,2H).¹³C NMR(126MHz,Acetone-d₆)169.42,139.28,138.22,135.41,131.56,130.12(2C),128.80,128.45(2C),126.85,123.71,121.63,116.58(t,J＝258.3Hz),113.10,108.66,42.31,31.04,27.46.

EXAMPLE 11 Synthesis of Compound C11

(1) Synthesis of intermediate M13

Sodium hydride (60% in mineral oil, 80mg, 2.0mmol) was dissolved in N, N-dimethylformamide (2.0mL) at room temperature, and then a solution of intermediate M9(170mg, 0.5mmol) in N, N-dimethylformamide (1.0mL) was added dropwise to the above system, after the addition was complete, the reaction was carried out at 40 ℃ for 30 minutes. N, N-dimethylaminoethane hydrobromide (291mg, 1.25mmol) was then added to the system and reacted at 40 ℃ overnight. After the reaction was completed, the reaction solution was poured into ice water to quench the reaction, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and purified by column chromatography to obtain intermediate M13(161mg) as a white solid with a yield of 78%.¹H NMR(400MHz,CDCl₃)7.95(d,J＝8.4Hz,1H),7.26(d,J＝8.4Hz,2H),7.00(d,J＝8.4Hz,2H),6.85(s,1H),6.73(d,J＝8.4Hz,1H),5.55(s,2H),3.89(s,3H),3.77(d,J＝28.2Hz,4H),3.08–2.94(m,2H),2.69(s,2H),2.39(s,6H)。

(2) Synthesis of Compound C11

The starting material was replaced by M13 and reacted in polyphosphoric acid according to the method of example 1 to give compound C11 as a white solid in 67% yield. Purity: 95 percent.¹H NMR(400MHz,CDCl₃)8.04(s,1H),7.93(d,J＝8.4Hz,1H),7.28(d,J＝1.7Hz,2H),7.10(d,J＝8.4Hz,2H),6.69(d,J＝8.4Hz,1H),4.04(s,2H),3.95(s,3H),3.80(s,4H),2.96–2.89(m,2H),2.71(s,2H),2.39(s,6H).¹³C NMR(126MHz,CDCl₃)169.36,148.15,136.75,132.52,132.32,129.80(2C),128.90(2C),127.30,125.93,124.98,118.02,113.05,102.12,57.11,55.42,50.29,48.26,45.44,31.78,26.61.HRMS(ESI)m/z calcd C₂₃H₂₆N₃O₂Cl[M+H]^-410.1641,found 410.1647。

EXAMPLE 12 Synthesis of Compound C12

(1) Synthesis of intermediate M14

The procedure of example 11 was followed, substituting M9 for the starting material, and reacting with 3-bromo-N, N-dimethyl-1-propylamine hydrobromide to give intermediate M14 as a white solid in 57% yield.¹H NMR(400MHz,CDCl₃)7.95(d,J＝8.4Hz,1H),7.27(d,J＝10.1Hz,2H),6.99(d,J＝8.3Hz,2H),6.85(s,1H),6.73(d,J＝8.4Hz,1H),5.54(s,2H),3.88(s,3H),3.71(s,4H),3.00(d,J＝4.0Hz,2H),2.46(t,J＝7.4Hz,2H),2.32(s,6H),2.01–1.84(m,2H)。

(2) Synthesis of Compound C12

The starting material was replaced by M14 and reacted in polyphosphoric acid according to the method of example 1 to give compound C12 as a white solid in 24% yield. Purity: 95 percent.¹H NMR(400MHz,CDCl₃)8.11(s,1H),7.92(d,J＝8.4Hz,1H),7.30(d,J＝3.6Hz,2H),7.13(d,J＝8.3Hz,2H),6.71(d,J＝8.4Hz,1H),4.06(s,2H),3.97(s,3H),3.76(s,4H),3.00–2.88(m,4H),2.65(s,6H),2.24–2.13(m,2H)。

EXAMPLE 13 Synthesis of Compound C13

(1) Synthesis of intermediate M15

The starting material was replaced by M9 and reacted with 2-bromoethyl methyl ether following the procedure of example 11 to give intermediate M15 as a white solid in 81% yield.¹H NMR(400MHz,CDCl₃)7.96(d,J＝8.4Hz,1H),7.25(d,J＝8.4Hz,2H),6.99(d,J＝8.4Hz,2H),6.84(s,1H),6.73(d,J＝8.4Hz,1H),5.55(s,2H),3.88(s,3H),3.83(d,J＝22.9Hz,4H),3.70(t,J＝5.3Hz,2H),3.40(s,3H),3.01(s,2H)。

(2) Synthesis of Compound C13

The starting material was replaced by M15 and reacted in polyphosphoric acid according to the procedure for example 1 to give compound C13 as a white solid in 35% yield. Purity: 98 percent.¹H NMR(400MHz,CDCl₃)8.00(s,1H),7.97(d,J＝8.3Hz,1H),7.31(d,J＝7.5Hz,2H),7.12(d,J＝8.3Hz,2H),6.72(d,J＝8.4Hz,1H),4.06(s,2H),3.97(s,3H),3.84(s,4H),3.71(t,J＝5.3Hz,2H),3.40(s,3H),2.99–2.91(m,2H).¹³C NMR(126MHz,CDCl₃)169.35,148.06,136.71,132.58,132.10,129.83(2C),128.93(2C),127.35,125.90,124.98,118.24,113.39,102.15,71.82,58.88,55.42,51.29,50.52,31.81,26.42.HRMS(ESI)m/z calcd C₂₂H₂₃N₂O₃Cl[M+H]⁺399.1470,found399.1459。

EXAMPLE 14 Synthesis of Compound C14

(1) Synthesis of intermediate M16

The starting material was replaced by M9 and reacted with 3-bromopropylmethyl ether following the procedure of example 11 to give intermediate M16 as a white solid in 66% yield.¹H NMR(400MHz,CDCl₃)7.94(d,J＝8.4Hz,1H),7.23(d,J＝8.4Hz,2H),6.97(d,J＝8.3Hz,2H),6.83(s,1H),6.71(d,J＝8.4Hz,1H),5.53(s,2H),3.86(s,3H),3.70(s,4H),3.49(t,J＝6.2Hz,2H),3.35(s,3H),3.03–2.95(m,2H),2.05–1.92(m,2H)。

(2) Synthesis of Compound C14

The starting material was replaced by M16 and reacted in polyphosphoric acid according to the method of example 1 to give compound C14 as a white solid with 29% yield. Purity: 99 percent.¹H NMR(400MHz,CDCl₃)8.10(s,1H),7.96(d,J＝8.4Hz,1H),7.29(d,J＝7.1Hz,2H),7.12(d,J＝8.4Hz,2H),6.71(d,J＝8.4Hz,1H),4.06(s,2H),3.96(s,3H),3.74(s,4H),3.51(t,J＝6.2Hz,2H),3.37(s,3H),2.93(s,2H),2.07–1.93(m,2H).¹³CNMR(126MHz,CDCl₃)168.20,146.99,135.63,131.58,131.10,128.79(2C),127.91(2C),126.23,124.87,123.93,117.31,112.13,101.13,69.49,57.63,54.39,48.89,46.76,30.80,27.41,25.65.HRMS(ESI)m/z calcd C₂₃H₂₅N₂O₃Cl[M+H]⁺413.1626,found 413.1625。

EXAMPLE 15 Synthesis of Compound C15

(1) Synthesis of intermediate M17

The starting material was replaced by M9 and reacted with 4-bromobutyl methyl ether following the procedure of example 11 to give intermediate M17 as a white solid in 86% yield.¹H NMR(400MHz,CDCl₃)7.96(d,J＝8.4Hz,1H),7.25(d,J＝8.4Hz,2H),7.00(d,J＝8.4Hz,2H),6.84(s,1H),6.73(d,J＝8.4Hz,1H),5.55(s,2H),3.88(s,3H),3.69(s,4H),3.46(t,J＝6.3Hz,2H),3.36(s,3H),3.03–2.91(m,2H),1.83–1.74(m,2H),1.71–1.62(m,2H)。

(2) Synthesis of Compound C15

The starting material was replaced by M17 and reacted in polyphosphoric acid and the procedure of example 1 was followed to give compound C15 as a white solid in 43% yield. Purity: 97 percent.¹H NMR(400MHz,CDCl₃)8.21(s,1H),7.96(d,J＝8.4Hz,1H),7.29(d,J＝2.1Hz,2H),7.11(d,J＝8.4Hz,2H),6.70(d,J＝8.4Hz,1H),4.05(s,2H),3.95(s,3H),3.66(s,4H),3.45(t,J＝6.3Hz,2H),3.35(s,3H),2.92(s,2H),1.80–1.73(m,2H),1.71–1.65(m,2H).¹³C NMR(126MHz,Acetone-d₆)168.27,148.19,138.67,133.49,133.35,131.39,130.10(2C),128.36(2C),127.40,125.11,118.67,112.52,101.46,72.13,57.57,54.85,49.26(d,J＝4.1Hz),31.13,28.49,27.05,26.72,24.79.HRMS(ESI)m/z calcdC₂₄H₂₇N₂O₃Cl[M+H]⁺427.1783,found 427.1781.。

EXAMPLE 16 Synthesis of Compound C16

(1) Synthesis of intermediate M18

The starting material was replaced by M9 and reacted with 1-bromo-2- (2-methoxyethoxy) ethane to give intermediate M18 as in example 11,white solid, yield 54%.¹H NMR(400MHz,CDCl₃)7.95(d,J＝8.3Hz,1H),7.25(d,J＝8.4Hz,2H),7.00(d,J＝8.3Hz,2H),6.84(s,1H),6.73(d,J＝8.4Hz,1H),5.55(s,2H),3.88(s,4H),3.84–3.77(m,4H),3.69–3.64(m,2H),3.58–3.54(m,2H),3.39(s,3H),3.01(s,2H)。

(2) Synthesis of Compound C16

The starting material was replaced by M18 and reacted in polyphosphoric acid according to the method of example 1 to give compound C16 as a white solid in 24% yield. Purity: 96 percent.¹H NMR(400MHz,CDCl₃)8.05(s,1H),7.95(d,J＝8.3Hz,1H),7.30(d,J＝7.5Hz,2H),7.12(d,J＝8.3Hz,2H),6.71(d,J＝8.4Hz,1H),4.06(s,2H),3.97(s,3H),3.85(dd,J＝10.2,5.4Hz,4H),3.80(t,J＝5.2Hz,2H),3.68–3.63(m,2H),3.60–3.49(m,2H),3.38(s,3H),2.95(s,2H).¹³C NMR(126MHz,CDCl₃)169.44,148.13,136.89,132.44,132.30,129.80(2C),128.84(2C),127.38,125.81,124.99,118.17,113.28,102.04,71.89,70.34,70.21,59.01,55.40,51.30,50.49,31.77,26.40.HRMS(ESI)m/zcalcd C₂₄H₂₄N₂O₄Cl[M+H]^-441.1587,found 441.1585。

EXAMPLE 17 Synthesis of Compound C17

(1) Synthesis of intermediate M19

The starting material was replaced by reaction of M9 with methyl 3-bromopropionate and the procedure of example 11 was followed to give intermediate M19 as a white solid in 57% yield.

(2) Synthesis of Compound C17

Replacement of the starting material with M19 in polyphosphoric acid and the procedure of example 1 was followed to giveCompound C17, white solid, yield 35%. Purity: 99 percent.¹H NMR(400MHz,CDCl₃)8.14(s,1H),7.96(d,J＝8.3Hz,1H),7.29(d,J＝5.7Hz,2H),7.11(d,J＝8.0Hz,2H),6.71(d,J＝8.4Hz,1H),4.05(s,2H),3.96(s,3H),3.93(s,2H),3.78(s,2H),3.71(s,3H),2.93(s,2H),2.80(s,2H).¹³C NMR(126MHz,CDCl₃)172.94,169.51,148.27,136.67,132.58,132.40,129.82(2C),128.92(2C),127.30,126.04,124.98,117.70,112.94,102.15,55.47,51.75,50.75,47.19,33.33,31.83,26.75.HRMS(ESI)m/z calcd C₂₃H₂₃N₂O₄Cl[M+H]⁺427.1419,found 427.1419。

EXAMPLE 18 Synthesis of Compound C18

Compound C17(63mg, 0.15mmol) was dissolved in methanol and tetrahydrofuran (2mL) and reacted at 40 ℃ for 3 hours. After the reaction is finished, the pH of the system is adjusted to about 4 by using 1M dilute hydrochloric acid, and a white precipitate is generated in the system. The filter cake obtained by the filtration was purified by column chromatography to obtain product C18(50mg) as a white solid with a yield of 80%. Purity: 98 percent.¹H NMR(400MHz,MeOD)7.75(d,J＝8.4Hz,1H),7.24(d,J＝8.2Hz,2H),7.16(d,J＝8.1Hz,2H),6.72(d,J＝8.4Hz,1H),4.05(s,2H),3.97(s,3H),3.85(s,2H),3.72(s,2H),2.89(s,2H),2.66(s,2H).¹³C NMR(126MHz,DMSO-d₆)168.65,148.49,139.13,134.52,131.11,130.58(2C),128.78(2C),127.37,125.11,124.84,117.96,111.95,101.94,55.74,49.97,46.74,31.28,29.49,26.75.HRMS(ESI)m/z calcd C₂₂H₂₁N₂O₄Cl[M+H]⁺413.1263,found 413.1262。

EXAMPLE 19 Synthesis of Compound C19

Compound C18(20mg, 0.05mmol), HATU (46mg, 0.12mmol) and methylamine hydrochloride (7.0mg, 0.1mmol) were dissolved in N, N-dimethylformamide (1.0mL) and DI was addedPEA (25. mu.L, 0.15mmol) was reacted at room temperature overnight. After the reaction was completed, the system was diluted with ethyl acetate, washed with water three times, the organic layer was dried over anhydrous sodium sulfate, and column chromatography was performed to obtain product C19(8.3mg) as a white solid with a yield of 39%. Purity: 99 percent.¹H NMR(400MHz,MeOD)8.06(s,1H),7.74(d,J＝8.3Hz,1H),7.24(d,J＝7.8Hz,2H),7.16(d,J＝7.9Hz,2H),6.73(d,J＝8.4Hz,1H),4.05(s,2H),3.98(s,3H),3.87(s,2H),3.71(s,2H),2.86(s,2H),2.68(s,3H),2.56(s,2H).¹³C NMR(126MHz,DMSO-d₆)171.50,168.55,148.46,139.17,134.54,131.11,130.60(2C),128.77(2C),127.39,125.02,124.81,118.03,111.92,101.92,55.74,50.25,47.31,35.00,31.31,26.71,25.90.HRMS(ESI)m/z calcd C₂₃H₂₄N₃O₃Cl[M+H]⁺426.1579,found 426.1577。

EXAMPLE 20 Synthesis of Compound C20

(1) Synthesis of intermediate M20

The starting material was replaced with methyl 3- (2-nitrovinyl) -1H-indole-4-carboxylate and reacted with sodium borohydride according to the procedure for example 1 to give intermediate M20 as a white solid in 70% yield.¹H NMR(400MHz,CDCl₃)8.36(s,1H),7.80(d,J＝7.5Hz,1H),7.54(d,J＝8.1Hz,1H),7.21(t,J＝7.8Hz,1H),7.18(d,J＝2.3Hz,1H),4.70(t,J＝6.6Hz,2H),3.95(s,3H),3.67(t,J＝6.6Hz,2H)。

(2) Synthesis of intermediate M21

The starting material was replaced by M20 and reacted under Pd/C, hydrogen conditions according to the procedure for example 1 to give intermediate M21 as a white solid in 50% yield.¹H NMR(400MHz,DMSO)11.11(s,1H),7.98(s,1H),7.66(d,J＝7.4Hz,1H),7.53(d,J＝7.9Hz,1H),7.26(s,1H),7.17(t,J＝7.7Hz,1H),3.41(s,2H),2.93(s,2H)。

(3) Synthesis of intermediate M22

The procedure of example 1 was followed, substituting M21 for the starting material and reacting with 4-chlorobenzyl bromide, to give intermediate M22 as a white solid in 85% yield.¹H NMR(400MHz,CDCl₃)7.99(d,J＝7.5Hz,1H),7.38(d,J＝8.1Hz,1H),7.28(dd,J＝8.0,4.7Hz,3H),7.03(d,J＝8.3Hz,2H),6.97(s,1H),6.50(s,1H),5.27(s,2H),3.62(dd,J＝9.7,5.5Hz,2H),3.10–3.02(m,2H)。

(4) Synthesis of the end product C20

The starting material was replaced by M22 and reacted in polyphosphoric acid according to the procedure of example 1 to give the final product C20 as a white solid in 35% yield. Purity: 99 percent.¹H NMR(400MHz,DMSO-d₆)11.14(s,1H),7.97(t,J＝5.7Hz,1H),7.65(d,J＝7.4Hz,1H),7.45(d,J＝7.9Hz,1H),7.35(d,J＝8.4Hz,2H),7.25(d,J＝8.4Hz,2H),7.12(t,J＝7.7Hz,1H),4.06(s,2H),3.46–3.37(m,2H),2.87(s,2H).¹³C NMR(126MHz,DMSO-d₆)170.38,138.83,136.35,134.89,131.29,130.66(2C),128.88(2C),126.06,124.41,122.37,120.55,114.58,111.58,42.47,31.40,27.82.HRMS(ESI)m/z calcdC₁₈H₁₅N₂OCl[M+H]⁺311.0946,found 311.0947。

EXAMPLE 21 Synthesis of Compound C21

(1) Synthesis of intermediate M23

The starting material was replaced with 7-isopropoxy-3- (2-nitrovinyl) -1H-indole-4-carboxylic acid methyl ester and reacted with sodium borohydride to give intermediate M23 as a white solid in 70% yield as per example 1.¹H NMR(400MHz,CDCl₃)8.52(s,1H),7.87(d,J＝8.4Hz,1H),7.16(d,J＝2.5Hz,1H),6.65(d,J＝8.4Hz,1H),4.91–4.78(m,1H),4.73(t,J＝6.6Hz,2H),3.93(s,3H),3.72(t,J＝6.6Hz,2H),1.45(d,J＝6.1Hz,6H)。

(2) Synthesis of intermediate M24

The starting material was replaced by M23 and reacted under Pd/C, hydrogen conditions according to the procedure for example 1 to give intermediate M24 as a white solid in 90% yield.¹H NMR(400MHz,Acetone-d₆)10.23(s,1H),7.81(d,J＝8.3Hz,1H),7.15(s,1H),7.01(s,1H),6.78(d,J＝8.3Hz,1H),4.92–4.78(m,1H),3.57–3.49(m,2H),3.03–2.92(m,2H),1.39(d,J＝6.0Hz,6H)。

(3) Synthesis of intermediate M25

The procedure of example 1 was followed, substituting M24 for the starting material and reacting with 4-chlorobenzyl bromide, to give intermediate M25 as a white solid in 70% yield.

(4) Synthesis of intermediate M26

The starting material was replaced by M25 and reacted with 3-bromopropylmethyl ether following the procedure of example 11 to give intermediate M26 as a white solid in 80% yield.¹H NMR(400MHz,CDCl₃)7.94(d,J＝8.4Hz,1H),7.26(d,J＝21.1Hz,3H),6.92(d,J＝8.3Hz,2H),6.84(s,1H),6.69(d,J＝8.5Hz,1H),5.58(s,2H),4.80–4.66(m,1H),3.73(s,4H),3.52(t,J＝6.3Hz,2H),3.38(s,3H),3.04–2.98(m,2H),2.07–1.93(m,2H),1.23(d,J＝5.9Hz,6H)。

(5) Synthesis of intermediate M27

Replacing the raw material with M26 to react in polyphosphoric acid according to the formulaThe procedure of example 1 gave the final product M27 as a white solid in 30% yield.¹H NMR(400MHz,CDCl₃)9.70(s,1H),7.77(d,J＝8.3Hz,1H),7.08(d,J＝8.3Hz,2H),6.91(d,J＝8.3Hz,2H),6.61(d,J＝8.3Hz,1H),3.91(s,2H),3.73(s,4H),3.43(t,J＝6.0Hz,2H),3.30(s,3H),2.90(s,2H),1.94(s,2H)。

(5) Synthesis of the end product C21

Intermediate M27(40mg, 0.1mmol) was dissolved in 2.0mL acetonitrile: water 1:1, potassium hydroxide (56mg, 1.0mmol) was added under ice-cooling, and after the system was clarified, diethyl bromofluoromethylphosphonate (0.5mmol) was added dropwise. The reaction was carried out at room temperature for 15 minutes. The reaction was quenched with ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography to give product C21(27mg) as a white solid in 60% yield. Purity: 99 percent.¹H NMR(400MHz,CDCl₃)8.25(s,1H),7.94(d,J＝8.3Hz,1H),7.31(d,J＝8.4Hz,2H),7.12(d,J＝8.4Hz,2H),6.96(d,J＝8.3Hz,1H),6.66(t,J＝73.8Hz,1H),4.08(s,2H),3.75(br s,4H),3.51(t,J＝6.2Hz,2H),3.37(s,3H),2.94(brs,2H),2.08–1.96(m,2H).¹³C NMR(126MHz,CDCl₃)168.54,138.77,136.34,133.94,132.67,129.72(2C),128.95(2C),128.65,126.63,124.95,122.49,116.08(t,J＝260.9Hz),113.32,109.78,70.38,58.65,49.83,47.91,31.78,28.32,26.53.HRMS(ESI)m/zcalcd C₂₃H₂₃N₂O₃F₂Cl[M+H]^-447.1293,found447.1287。

EXAMPLE 22 Synthesis of Compound C11 hydrochloride

Compound C11(206mg,0.5mmol) was dissolved in 20mL of dichloromethane, a solution of 4M HCl in 1, 4-dioxane (1.5mL,6.0mmol) was added to the system, the reaction was stirred at room temperature for 1 hour, and the precipitated solid was filtered and washed with dichloromethane to give the product C11-HCl as a white solid in 95% yield.¹H NMR(400MHz,CDCl₃)8.04(s,1H),7.93(d,J＝8.4Hz,1H),7.28(d,J＝1.7Hz,2H),7.10(d,J＝8.4Hz,2H),6.69(d,J＝8.4Hz,1H),4.04(s,2H),3.95(s,3H),3.80(s,4H),2.96–2.89(m,2H),2.71(s,2H),2.39(s,6H)。

Example 23 inhibition Activity of Compounds on PDE5 enzyme

The test compound was conjugated with a peptide containing recombinant PDE5A1 protein (see Bioorganic: for methods of preparation of the recombinant protein)&Medicinal Chemistry Letters, 2012, volume 22, page number: 3261-3264), 20mM Tris-HCl, pH 7.5,2mM dithiothreitol (dithiothreitol), 10mM MgCl₂And 30,000cpm³H-cGMP was incubated for 15 min at room temperature and then separately incubated with 0.2M ZnSO₄And Ba (OH)₂The reaction was stopped and the unreacted content of the supernatant was measured using a Perkinelmer 2910 counter³H-cGMP, measured at least three times per molecule. IC for inhibition of PDE5A1 protein activity₅₀Values were calculated by concentration testing and non-linear regression.

The data of the test for the inhibitory activity of the compounds of the examples on the PDE5 enzyme are shown in Table 1 (IC for the inhibitory activity of the positive control Sildenafil on the PDE5 enzyme under equivalent conditions, IC)₅₀At 5.1 nM).

TABLE 1 inhibitory Activity of Compounds on PDE5 enzyme test results

As can be seen from the results in Table 1, the substituted benzazolazepine compounds of the present invention have good inhibitory activity on phosphodiesterase type 5, wherein the inhibitory effect of compounds C5, C8, C10, C11, C16, C18 and C19 on PDE5 enzyme is in the range of 20-60 nM; the inhibitory effect of compounds C14, C15, C17 and C21 on the PDE5 enzyme was in nM level, comparable to the positive drug sildenafil. Therefore, the substituted benzazepine compound has wide application space as a phosphodiesterase type 5 inhibitor.

Example 24 in vivo study of the pharmacological Effect of Compound C21 in anti-pulmonary hypertension animals

Pharmacodynamic studies of anti-pulmonary hypertension were conducted using compound C21 as a representative. The experimental animal model adopts 'rat intraperitoneal injection unconjugated alkaloid induced PAH experimental animal model' which has been successfully constructed and applied for many times in earlier research of the patent applicant. 60 SPF-grade male wistar rats weighing 220-250g were randomly divided into 4 groups, namely a normal group, a model group and an administration group (2.5mg/kg) as a positive control sildenafil group (5.0 mg/kg).

The modeling and administration method comprises the following steps: animals after random grouping are bred for three days, except normal control groups are given physiological saline, 2% monocrotaline (60mg/kg) is injected into abdominal cavity of the model group and each administration group at one time to construct a rat pulmonary hypertension model. Dosing was then started the next day, 1 time per day, for 4 consecutive weeks, and the mass of each group of rats was recorded daily. All the related animal experiments follow the relevant regulations of our country on the welfare and ethics of experimental animals.

Rat mean pulmonary artery pressure assay: adopting right cardiac catheterization method, after 1h of last administration, injecting 3% sodium pentobarbital (45mL/kg) into abdominal cavity of rats for anesthesia, fixing the rats on an operating table in the upward position after anesthesia, performing incision at the center of neck of the rats, dissociating right external jugular vein, and adopting right cardiac catheterization and heparin anticoagulation. The catheter is inserted from the right external jugular vein through the superior vena cava, right atrium, right ventricle, and into the pulmonary artery. The other end of the catheter is connected with a pressure sensor and a Med-Lab-U/8c biological signal acquisition system, pulmonary artery pressure at 10 minutes, pulmonary artery pressure at 30 minutes and pulmonary artery pressure at 60 minutes are respectively recorded, the pulmonary artery pressure is continuously recorded for 30 seconds, and the average value of the pulmonary artery pressure is taken as the average pulmonary artery pressure.

Preparing lung tissue specimens and calculating related indexes: the upper and middle two leaves of the right lung and the lower leaf tissue of the left lung of a rat are taken, the size of about 1.0cm multiplied by 2.0cm is rinsed by normal saline, the rat is immediately fixed in 10 percent neutral formaldehyde, and the rat is subjected to tissue block repairing, dehydration, paraffin embedding, slicing, HE staining and photographing under a light lens for observation. Each group of rats randomly selected 100-200 μm pulmonary muscle arterioles, measured the inner and outer diameters thereof, and calculated the ratio of the media thickness of the pulmonary arterioles to the outer diameter of the blood vessels for evaluating the media thickening degree (WT%) of the pulmonary arterioles. Taking the heart, separating and weighing the Right Ventricle (RV) and the left ventricle plus ventricular septum (LV + S), and taking the ratio of RV/(LV + S) as the right heart hypertrophy index (RVHI). The results of the experiment are shown in FIG. 1.

From the above results, it can be seen that the pulmonary artery pressure of the rats in the model group is significantly increased, the wall of the pulmonary arteriole is thickened and the arterial lumen is narrowed compared with the normal group; compared with the model group of rats, the positive drug sildenafil group and the compound C21 group can obviously reduce the pulmonary artery pressure and the right heart hypertrophy index, and the compound C21 group can show similar drug effect only by the dose of the positive drug sildenafil 1/4. Therefore, the test drug C21 has a good pharmacological effect of reducing pulmonary arterial pressure, and can be further developed into a new drug for treating pulmonary hypertension.

It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A substituted benzazepine compound characterized by having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof:

2. The substituted benzazolazepine compound of claim 1, wherein R is₁Selected from hydrogen, C_1-6Alkane, C_1-6Ethereal hydrocarbyl radical, C_1-6Alkylamino radical, C_1-5Carboxylic acid, C_1-5Carboxylic acid ester, C_1-5An alkylamide group;

3. The substituted benzazolazepine compound of claim 2, wherein R is₁Selected from hydrogen,

4. The substituted benzazolazepine compound of claim 2, wherein R is₂Is selected from

The R is₃Selected from hydrogen, fluoro, hydroxy, methoxy or difluoromethoxy.

5. The substituted benzazolepinone compound of any one of claims 1 to 4, wherein the pharmaceutically acceptable salt of the substituted benzazolepinone compound is a product obtained by reacting a compound of formula (I) with an acid.

6. A process for the preparation of substituted benzazolazepinones according to any one of claims 1 to 4, wherein R is₃To remove C_2-3When the substituent or the non-substituent alkoxy is other than the substituent or the non-substituent alkoxy, the method comprises the following steps:

wherein R is₄Is isopropyl, benzhydryl, dialkyl methyl or diaryl methyl, and the alkyl in the dialkyl methyl is C_1-5The aryl in the diarylmethyl is substituted or unsubstituted phenyl.

7. The method for preparing substituted benzazolyl-azaketones according to claim 6, wherein the reducing agent in steps S1 and S11 is one or more of sodium borohydride, lithium borohydride, potassium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride;

the reducing agent in the steps S2 and S21 is one or more of palladium, palladium carbon, palladium hydroxide, platinum carbon, platinum dioxide or nickel;

the alkaline substances in the steps S3, S4, S31, S41 and S61 are respectively one or more of sodium hydroxide, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, potassium tert-butoxide, sodium hydride, lithium bistrimethylsilyl amide, sodium bistrimethylsilyl amide, potassium bistrimethylsilyl amide or lithium diisopropylamide;

the acidic substance in step S5 is one or more of polyphosphoric acid, aluminum trichloride, concentrated sulfuric acid, or acetic anhydride.

8. Use of a substituted indolocarbazepine compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as a phosphodiesterase type 5 inhibitor.

9. Use of a substituted indolocarbazepine compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease associated with phosphodiesterase type 5.

10. The use of claim 9, wherein the medicament is in the form of oral tablets, pills, capsules, injection solution for injection, powder for injection, transdermal or subcutaneous absorbent.