CN111662299B - Substituted indolocazazepine compound and preparation method and application thereof - Google Patents

Substituted indolocazazepine compound and preparation method and application thereof Download PDF

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CN111662299B
CN111662299B CN202010660872.6A CN202010660872A CN111662299B CN 111662299 B CN111662299 B CN 111662299B CN 202010660872 A CN202010660872 A CN 202010660872A CN 111662299 B CN111662299 B CN 111662299B
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罗海彬
吴德燕
姜赞
黄仪有
周倩
黄雅丹
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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 inhibitory action on phosphodiesterase type 5, namely the compound can be used as a phosphodiesterase type 5 inhibitor to prepare medicaments for treating and/or preventing related diseases caused by 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.
Figure DDA0002578517590000011

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 then also 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 (Sildenafil, Viagra), Tadalafil (Cialis), Vardenafil (virdenafil, Levitra), Avanafil (Avanafil, Stendra) are drugs for treating erectile dysfunction, and Sildenafil and Tadalafil were approved as novel targeted anti-PAH drugs in 2005 and 2009, respectively, thereafter. In addition, PDE5 inhibitors have been found to be useful in improving memory, combating tumors, treating pulmonary disorders, treating cardiac disorders, and the like. Nevertheless, the current 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 PDE5 selective 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 purpose of the invention is realized by the following scheme:
a substituted benzazepine compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof:
Figure BDA0002578517570000021
wherein R is 1 Selected from hydrogen, C 1-6 Substituted or unsubstituted alkane, C 1-6 Substituted or unsubstituted cycloalkanes;
R 2 selected from substituted or unsubstituted benzyl, C 1-6 Substituted or unsubstituted alkanes, C 1-6 Substituted or unsubstituted cycloalkane;
R 3 selected from hydrogen, deuterium, halogen, hydroxyl, sulfydryl, carboxyl, sulfonic acid group, methylsulfonyl, C 1-3 Substituted or unsubstituted alkoxy;
wherein said C 1-6 Substituted or unsubstituted alkanes, C 1-6 Substituted or unsubstituted cycloalkane, C 1-3 The substituent in the substituted or unsubstituted alkoxy group is C 1-3 Alkoxy radical, C 1-3 Etheralkyl radical, C 1-3 Carboxylic acid, C 1-3 Carboxylic acid ester, C 1-3 Amino or C 1-3 An amide group;
the substituent in the substituted or unsubstituted benzyl is halogen or C 1-3 Alkyl radical, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 One or more of haloalkoxy.
Preferably, said R is 1 Selected from hydrogen, C 1-6 Alkane, C 1-6 Ether hydrocarbon group, C 1-6 Alkylamino radical, C 1-5 Carboxylic acid, C 1-5 Carboxylic acid ester, C 1-5 An alkanoylamino group;
the R is 2 Is selected from substituted or unsubstituted benzyl, wherein the substituent is one or more of halogen, methyl, ethyl, methoxy and ethoxy;
the R is 3 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, carboxyl, methoxy, ethoxy, fluoromethoxy, fluoroethoxy, chloromethoxy or chloroethoxy.
Preferably, said R is 1 Selected from hydrogen,
Figure BDA0002578517570000022
Figure BDA0002578517570000031
Preferably, said R is 2 Is selected from
Figure BDA0002578517570000032
Said R is 3 Selected from hydrogen, fluorine, hydroxyl, methoxy or difluoromethoxy.
Preferably, the structure of the substituted benzazepine compound is shown as one of the following:
Figure BDA0002578517570000033
。
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 protects theProcess for the preparation of substituted indoxazolones when R is 3 To remove C 2-3 When the substituent or the non-substituent alkoxy is other than the 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);
Figure BDA0002578517570000041
when R is 3 Is C 2-3 When 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, and gradually heating to 25-100 ℃ for reaction 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 agent, and gradually heating to 25-100 ℃ for reaction to obtain a compound shown in the formula (I);
Figure BDA0002578517570000042
wherein R is 4 Is isopropyl, benzhydryl, dialkyl methyl or diaryl methyl, and the alkyl in the dialkyl methyl is C 1-5 Substituted or unsubstituted alkane, wherein the 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, dimethylsulfoxide, 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 the 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 material 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 of dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide, N-methylpyrrolidone, 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 benzazepine compound or the pharmaceutically acceptable salt thereof in preparing medicaments 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 for injection and 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 benzazepine 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
Figure BDA0002578517570000071
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, and then 3.0mL of methanol was slowly added dropwise, and the reaction was carried out for 1 hour under ice bath conditions. After the reaction was completed, a saturated ammonium chloride solution was added to quench the reaction, the system was concentrated to remove most of the organic solvent, and then extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and column chromatography was performed to obtain intermediate M1(165mg) as a white solid with a yield of 62%. 1 H NMR(400MHz,CDCl 3 )δ8.56(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
Figure BDA0002578517570000072
Intermediate M1(266mg,1.0mmol) was dissolved in 10mL of methanol and Pd/C (30mg) was added and 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%. 1 H NMR(400MHz,DMSO)δ8.00(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
Figure BDA0002578517570000073
Intermediate M2(102mg, 0.5mmol) was dissolved in N, N-dimethylformamide (3.0mL) under ice bath and dry tube protection, sodium hydride (60% dispersed in mineral oil, 20mg, 0.5mmol) was slowly added to the system, after 30 minutes of reaction 4-fluorobenzyl bromide (95mg dissolved in 1.0mL of N, N-dimethylformamide) was added, and then the reaction was allowed to proceed 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%. 1 H NMR(400MHz,CDCl 3 )δ7.96(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
Figure BDA0002578517570000081
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, the system is poured into an ice-water mixed solution, ethyl acetate is used for extraction, water and saturated sodium chloride are respectively washed, dried by anhydrous sodium sulfate and separated by column chromatography to obtain a product C1(47mg) which is a white solid with the yield of 30%. Purity: 96 percent. 1 H NMR(400MHz,Acetone-d 6 )δ10.83(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). 13 C NMR(126MHz,Acetone-d 6 )δ169.65,161.48(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
Figure BDA0002578517570000082
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. 1 H NMR(400MHz,DMSO-d 6 )δ8.08(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 end product C2
Figure BDA0002578517570000091
The starting material was replaced by M4 and reacted in polyphosphoric acid according to the method of example 1 to give the final product C2 as a white solid with a yield of 40%. Purity: 97 percent. 1 H NMR(400MHz,DMSO-d 6 )δ11.69(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). 13 C NMR(126MHz,DMSO-d 6 )δ169.40,150.96(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 C 18 H 14 N 2 OFCl[M+H] + 239.0851,found 329.0858。
EXAMPLE 3 Synthesis of Compound C3
(1) Synthesis of intermediate M5
Figure BDA0002578517570000092
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. 1 H NMR(400MHz,CDCl 3 )δ7.97(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 end product C3
Figure BDA0002578517570000093
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. 1 H NMR(400MHz,CDCl 3 )δ8.49(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
Figure BDA0002578517570000101
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. 1 H NMR(400MHz,CDCl 3 )δ8.54(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
Figure BDA0002578517570000102
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
Figure BDA0002578517570000103
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. 1 H NMR(400MHz,CDCl 3 )δ7.99(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 end product C4
Figure BDA0002578517570000111
The starting material was replaced by M8 and reacted in polyphosphoric acid according to the method of example 1 to give the final product C4 as a white solid with a yield of 30%. Purity: 97 percent. 1 H NMR(400MHz,CDCl 3 )δ8.10(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). 13 C NMR(126MHz,DMSO-d 6 )δ170.27,162.12,160.20,148.61,136.33(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 C 19 H 17 N 2 O 2 F 2 [M+H] - 323.1201,found 323.1201。
EXAMPLE 5 Synthesis of Compound C5
(1) Synthesis of intermediate M9
Figure BDA0002578517570000112
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. 1 H NMR(400MHz,CDCl 3 )δ7.98(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
Figure BDA0002578517570000113
The starting material was replaced with M9 and reacted in polyphosphoric acid according to the method of example 1 to give compound C5 as a white solid with 51% yield. Purity: 95 percent. 1 H NMR(500MHz,CDCl 3 )δ8.27(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). 13 C NMR(126MHz,CDCl 3 )δ171.60,148.56,136.65,132.62,132.52,129.82(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 C 19 H 17 N 2 O 2 Cl 2 [M+H] + 341.1051,found 341.1047。
EXAMPLE 6 Synthesis of Compound C6
(1) Synthesis of intermediate M10
Figure BDA0002578517570000121
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
Figure BDA0002578517570000122
Replacing the raw material with M10 in the poly-polymerizationReaction in phosphoric acid followed the procedure of example 1 gave compound C6 as a white solid in 30% yield. Purity: 99 percent. 1 H NMR(400MHz,CDCl 3 )δ8.09(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). 13 C NMR(126MHz,DMSO-d 6 )δ170.26,148.62,139.61,134.41,131.68(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
Figure BDA0002578517570000123
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
Figure BDA0002578517570000131
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. 13 C NMR(126MHz,DMSO-d 6 )δ170.22,148.63,142.69,134.20,133.40,130.74,128.58,127.50,127.32,126.50,125.10,124.56,117.64,112.23,101.95,55.75,42.41,31.49,27.78.。
EXAMPLE 8 Synthesis of Compound C8
(1) Synthesis of intermediate M12
Figure BDA0002578517570000132
Replacement of the starting material by M7 reaction with 3-chloro-4-methoxybenzyl bromide following the procedure of example 1 gave intermediate M11 as a white solid in 86 yield％。 1 H NMR(400MHz,CDCl 3 )δ8.01(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
Figure BDA0002578517570000133
The starting material was replaced with M12 and reacted in polyphosphoric acid according to the method of example 1 to give compound C8 as a white solid with 30% yield. Purity: 95 percent. 1 H NMR(400MHz,CDCl 3 )δ8.12(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). 13 C NMR(126MHz,CDCl 3 )δ171.76,153.82,148.58,132.92,131.37,130.18(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 C 20 H 19 N 2 O 3 Cl[M+H] + 371.1157,found 371.1144。
EXAMPLE 9 Synthesis of Compound C9
Figure BDA0002578517570000141
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 ℃ for reaction for 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%. 1 H NMR(400MHz,DMSO-d 6 )δ10.99(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
Figure BDA0002578517570000142
Compound C9(33mg, 0.1mmol) was dissolved in a mixed solution of 3.0mL acetonitrile: water ═ 1:1, potassium hydroxide (56mg, 1.0mmol) was added in an 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. 1 H NMR(400MHz,Acetone-d 6 )δ10.66(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). 13 C NMR(126MHz,Acetone-d 6 )δ169.42,139.28,138.22,135.41,131.56,130.12(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
Figure BDA0002578517570000151
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, and after the addition was completed, the reaction was carried out at 40 ℃ for 30 minutes. N, N-dimethylamino bromoethane 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%. 1 H NMR(400MHz,CDCl 3 )δ7.95(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
Figure BDA0002578517570000152
The starting material was replaced with M13 and reacted in polyphosphoric acid according to the method of example 1 to give compound C11 as a white solid with 67% yield. Purity: 95 percent. 1 H NMR(400MHz,CDCl 3 )δ8.04(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). 13 C NMR(126MHz,CDCl 3 )δ169.36,148.15,136.75,132.52,132.32,129.80(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 C 23 H 26 N 3 O 2 Cl[M+H] - 410.1641,found 410.1647。
EXAMPLE 12 Synthesis of Compound C12
(1) Synthesis of intermediate M14
Figure BDA0002578517570000153
The procedure of example 11 was followed, substituting M9 for the reaction with 3-bromo-N, N-dimethyl-1-propylamine hydrobromide, to give intermediate M14 as a white solid in 57% yield. 1 H NMR(400MHz,CDCl 3 )δ7.95(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
Figure BDA0002578517570000161
The starting material was replaced with M14 and reacted in polyphosphoric acid according to the method of example 1 to give compound C12 as a white solid with 24% yield. Purity: 95 percent. 1 H NMR(400MHz,CDCl 3 )δ8.11(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
Figure BDA0002578517570000162
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. 1 H NMR(400MHz,CDCl 3 )δ7.96(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
Figure BDA0002578517570000163
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. 1 H NMR(400MHz,CDCl 3 )δ8.00(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). 13 C NMR(126MHz,CDCl 3 )δ169.35,148.06,136.71,132.58,132.10,129.83(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 C 22 H 23 N 2 O 3 Cl[M+H] + 399.1470,found399.1459。
EXAMPLE 14 Synthesis of Compound C14
(1) Synthesis of intermediate M16
Figure BDA0002578517570000171
The starting material was replaced with M9 and reacted with 3-bromopropylmethyl ether according to the method of example 11 to give intermediate M16 as a white solid in 66% yield. 1 H NMR(400MHz,CDCl 3 )δ7.94(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
Figure BDA0002578517570000172
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. 1 H NMR(400MHz,CDCl 3 )δ8.10(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). 13 C NMR(126MHz,CDCl 3 )δ168.20,146.99,135.63,131.58,131.10,128.79(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 C 23 H 25 N 2 O 3 Cl[M+H] + 413.1626,found 413.1625。
EXAMPLE 15 Synthesis of Compound C15
(1) Synthesis of intermediate M17
Figure BDA0002578517570000181
The starting material was replaced with 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. 1 H NMR(400MHz,CDCl 3 )δ7.96(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
Figure BDA0002578517570000182
The starting material was replaced with M17 and reacted in polyphosphoric acid according to the method of example 1 to give compound C15 as a white solid with 43% yield. Purity: 97 percent. 1 H NMR(400MHz,CDCl 3 )δ8.21(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). 13 C NMR(126MHz,Acetone-d 6 )δ168.27,148.19,138.67,133.49,133.35,131.39,130.10(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 calcd C 24 H 27 N 2 O 3 Cl[M+H] + 427.1783,found 427.1781.。
EXAMPLE 16 Synthesis of Compound C16
(1) Synthesis of intermediate M18
Figure BDA0002578517570000183
The starting material was replaced with M9 and reacted with 1-bromo-2- (2-methoxyethoxy) ethane following the procedure of example 11 to give intermediate M18 as a white solid in 54% yield. 1 H NMR(400MHz,CDCl 3 )δ7.95(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
Figure BDA0002578517570000191
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. 1 H NMR(400MHz,CDCl 3 )δ8.05(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). 13 C NMR(126MHz,CDCl 3 )δ169.44,148.13,136.89,132.44,132.30,129.80(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/z calcd C 24 H 24 N 2 O 4 Cl[M+H] - 441.1587,found 441.1585。
EXAMPLE 17 Synthesis of Compound C17
(1) Synthesis of intermediate M19
Figure BDA0002578517570000192
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
Figure BDA0002578517570000193
The starting material was replaced with M19 and reacted in polyphosphoric acid to obtain a compound according to the method of example 1Compound C17, white solid, yield 35%. Purity: 99 percent. 1 H NMR(400MHz,CDCl 3 )δ8.14(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). 13 C NMR(126MHz,CDCl 3 )δ172.94,169.51,148.27,136.67,132.58,132.40,129.82(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 C 23 H 23 N 2 O 4 Cl[M+H] + 427.1419,found 427.1419。
EXAMPLE 18 Synthesis of Compound C18
Figure BDA0002578517570000201
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 be about 4 by using 1M dilute hydrochloric acid, and white precipitate is generated in the system. The filter cake obtained by filtration was purified by column chromatography to give product C18(50mg) as a white solid in 80% yield. Purity: 98 percent. 1 H NMR(400MHz,MeOD)δ7.75(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). 13 C NMR(126MHz,DMSO-d 6 )δ168.65,148.49,139.13,134.52,131.11,130.58(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 C 22 H 21 N 2 O 4 Cl[M+H] + 413.1263,found 413.1262。
EXAMPLE 19 Synthesis of Compound C19
Figure BDA0002578517570000202
Compound C18(20mg, 0.05mmol), HATU (46mg, 0.12mmol) and methylamine hydrochloride (7.0mg, 0.1mmol) were dissolved in N,n-dimethylformamide (1.0mL), followed by DIPEA (25. mu.L, 0.15mmol) was added and reacted overnight at room temperature. 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. 1 H NMR(400MHz,MeOD)δ8.06(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). 13 C NMR(126MHz,DMSO-d 6 )δ171.50,168.55,148.46,139.17,134.54,131.11,130.60(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 C 23 H 24 N 3 O 3 Cl[M+H] + 426.1579,found 426.1577。
EXAMPLE 20 Synthesis of Compound C20
(1) Synthesis of intermediate M20
Figure BDA0002578517570000211
The starting material was replaced with methyl 3- (2-nitrovinyl) -1H-indole-4-carboxylate and reacted with sodium borohydride to give intermediate M20 as a white solid in 70% yield according to the procedure of example 1. 1 H NMR(400MHz,CDCl 3 )δ8.36(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
Figure BDA0002578517570000212
The starting material was replaced with M20 and reacted under Pd/C, hydrogen conditions to give intermediate M21 as a white solid in 50% yield according to the procedure of example 1. 1 H NMR(400MHz,DMSO)δ11.11(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
Figure BDA0002578517570000213
The starting material was replaced with M21 and reacted with 4-chlorobenzyl bromide following the procedure of example 1 to give intermediate M22 as a white solid in 85% yield. 1 H NMR(400MHz,CDCl 3 )δ7.99(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 end product C20
Figure BDA0002578517570000221
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. 1 H NMR(400MHz,DMSO-d 6 )δ11.14(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). 13 C NMR(126MHz,DMSO-d 6 )δ170.38,138.83,136.35,134.89,131.29,130.66(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 calcd C 18 H 15 N 2 OCl[M+H] + 311.0946,found 311.0947。
EXAMPLE 21 Synthesis of Compound C21
(1) Synthesis of intermediate M23
Figure BDA0002578517570000222
The starting material was replaced with 7-isopropoxy-3- (2-nitrovinyl) -1H-indole-4-carboxylic acid methyl ester and reacted with sodium borohydride according to the method of example 1Intermediate M23 was obtained in 70% yield as a white solid. 1 H NMR(400MHz,CDCl 3 )δ8.52(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
Figure BDA0002578517570000223
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. 1 H NMR(400MHz,Acetone-d 6 )δ10.23(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
Figure BDA0002578517570000231
The starting material was replaced by reaction of M24 with 4-chlorobenzyl bromide and the procedure of example 1 was followed to give intermediate M25 as a white solid in 70% yield.
(4) Synthesis of intermediate M26
Figure BDA0002578517570000232
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. 1 H NMR(400MHz,CDCl 3 )δ7.94(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
Figure BDA0002578517570000233
The starting material was replaced by M26 and reacted in polyphosphoric acid according to the procedure of example 1 to give the final product M27 as a white solid in 30% yield. 1 H NMR(400MHz,CDCl 3 )δ9.70(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
Figure BDA0002578517570000241
Intermediate M27(40mg, 0.1mmol) was dissolved in 2.0mL acetonitrile: 1 in water: 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. 1 H NMR(400MHz,CDCl 3 )δ8.25(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(br s,2H),2.08–1.96(m,2H). 13 C NMR(126MHz,CDCl 3 )δ168.54,138.77,136.34,133.94,132.67,129.72(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/z calcd C 23 H 23 N 2 O 3 F 2 Cl[M+H] - 447.1293,found447.1287。
EXAMPLE 22 Synthesis of Compound C11 hydrochloride
Figure BDA0002578517570000242
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. 1 H NMR(400MHz,CDCl 3 )δ8.04(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
Test Compounds and compositions 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 MgCl 2 And 30,000cpm 3 H-cGMP was incubated at room temperature for 15 min and then separately incubated with 0.2M ZnSO 4 And Ba (OH) 2 The reaction was stopped and the supernatant was measured for unreacted reagents using a PerkinElmer 2910 counter 3 H-cGMP, measured at least three times per molecule. IC for inhibition of PDE5A1 protein activity 50 Values 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) 50 At 5.1 nM).
TABLE 1 test results of the inhibitory Activity of Compounds on the PDE5 enzyme
Figure BDA0002578517570000251
As can be seen from the results in Table 1, the substituted benzazepine compounds of the present invention have excellent inhibitory activity against phosphodiesterase type 5, wherein the inhibitory activity of compounds C5, C8, C10, C11, C16, C18 and C19 against the 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 efficacy Studies of Compound C21 in anti-pulmonary hypertension animals
Pharmacodynamic studies on anti-pulmonary hypertension were performed 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 then started the next day, 1 time per day for 4 weeks with each group of rats mass 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 detection: adopting a right cardiac catheterization method, carrying out intraperitoneal injection on a rat with 3% pentobarbital sodium (45mL/kg) into an anesthetized animal after 1h of final administration, fixing the rat on an operating table in an upward position after anesthesia, carrying out incision on the middle of the neck of the rat, dissociating the right external jugular vein, and carrying out intubation on the right jugular vein by using a right cardiac catheter and carrying out heparin anticoagulation. The catheter was inserted from the right external jugular vein through the superior vena cava, right atrium, right ventricle, 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 a lung tissue specimen 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 physiological saline, the rat is immediately placed into 10 percent neutral formaldehyde for fixation, and the tissue is subjected to block repair, dehydration, paraffin embedding, slicing, HE staining and observation and photographing under a light mirror. 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 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 model rats, the positive drug sildenafil group and the compound C21 group can both significantly reduce pulmonary arterial pressure and the right heart hypertrophy index, and the compound C21 group can show similar drug effects only with 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 (6)

1. A substituted benzazepine compound characterized by having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0003671337440000011
wherein, R is 1 Selected from hydrogen,
Figure FDA0003671337440000012
Figure FDA0003671337440000013
R 2 Is substituted or unsubstituted benzyl, and the substituent in the substituted or unsubstituted benzyl is halogen or C 1-3 An alkoxy group;
R 3 is fluorine, methoxy or difluoromethoxy.
2. The substituted benzazepine compound according to claim 1, wherein the pharmaceutically acceptable salt of the substituted benzazepine compound is a product obtained by reacting a compound of formula (I) with an acid.
3. A process for the preparation of substituted benzazolazepinones according to claim 1 or 2, wherein R is 3 When the fluorine is methoxy or fluorine, 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);
Figure FDA0003671337440000021
when R is 3 When the compound is difluoromethoxy, 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-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, and gradually heating to 25-100 ℃ for reaction 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 agent, and gradually heating to 25-100 ℃ for reaction to obtain a compound shown in the formula (I);
Figure FDA0003671337440000022
，
wherein R is 4 Is a dialkyl methyl, and the alkyl in the dialkyl methyl is C 1-5 An alkane;
wherein, 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 the steps S5 and S51 is polyphosphoric acid;
the reducing agent in the steps S1 and S11 is one or more of sodium borohydride, lithium borohydride, potassium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride;
the reducing agent in steps S2 and S21 is one or more of palladium, palladium carbon, palladium hydroxide, platinum carbon, platinum dioxide or nickel.
4. Use of a substituted indolylazanone compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof for the preparation of a phosphodiesterase type 5 inhibitor.
5. Use of substituted indoxazanones according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with phosphodiesterase type 5.
6. The use of claim 5, wherein the medicament is in the form of oral tablets, pills, capsules, injection solution for injection, powder for injection, transdermal or subcutaneous absorbent.
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