CN113861193A - Method for preparing indolopyridyl tetralone and derivatives thereof by photoinitiated free radical series reaction and products - Google Patents

Abstract

The invention relates to a method for preparing indolopyridyl tetrahdione and derivatives thereof by photoinitiated free radical series reaction and a product, belonging to the technical field of organic compound preparation. The invention discloses a method for preparing indolyltetrahydropyridinedione and derivatives thereof by photoinitiated free radical series reaction, which mainly comprises the step of reacting indole derivatives and any one of acyl chloride or sulfonyl chloride in the presence of alkali in the presence of a facial type tri (2-phenylpyridine) iridium (fac-Ir (ppy)₃) The catalytic light reaction to obtain indolyltetrahydropyridine dione and its derivative, and belongs to serial cyclization reaction between Michael acceptor and free radical catalyzed by light redox. The preparation method of the photoinitiated free radical series reaction has wide free radical sources, and the free radical series strategy provides a simple solution for the simple synthesis of various indolyltetrahydropyridinedione derivatives.

Description

Method for preparing indolopyridyl tetralone and derivatives thereof by photoinitiated free radical series reaction and products

Technical Field

The invention belongs to the technical field of organic compound preparation, and relates to a method for preparing indolylpetrahydropyridinedione and derivatives thereof by photoinitiated free radical series reaction and a product.

Background

Heterocyclic compounds are one of the most important structures in chemical substances, and are prominent in pesticides, herbicides, natural products and drugs. It is estimated that more than 50% of the published chemical literature contains heterocyclic structures, 70% of the drug products have heterocyclic structures, and bicyclic aromatic heterocycles containing nitrogen atoms, such as quinoline, isoquinoline and indole, are ubiquitous in organic compounds in the biological and medical fields. In particular, to date, tens of thousands of biologically active indole derivatives have been identified. Of these, over 200 are currently labeled as drugs or are undergoing clinical trials. Furthermore, the indole nucleus is not only important in biological systems and pharmaceutical research, but is also an essential part in material science. Therefore, it would be of great interest to develop efficient methods for synthesizing polyfunctional indole derivatives.

Acyl radicals are generally nucleophilic species that have been widely used in the past decades for the addition of reactive olefins, acylation of heterocyclic aromatic hydrocarbons and the preparation of a wide variety of natural products and bioactive molecules. However, conventional methods for producing acyl groups generally require more severe reaction conditions, and these intermediates are generally obtained by: the alkyl radical is generated by photochemical or thermal initiation of alkyl iodide and then carbonylation is carried out by CO; providing an acyl radical by photochemical cleavage of rc (o) X-bonded acyl telluride (X ═ R, Te); by alpha-hydroxy or alpha-aminoketones RC (O) X (X ═ CH (OH) R or CH (NH)₂)R]Cyclic ketones (via norrish type cleavage), esters (via fries rearrangement), or acyl cobalt reagents can all deliver acyl radicals; hydrogen peroxide-mediated extraction of hydrogen atoms from aldehydes and α -keto acids is also a viable option for the generation of acyl radicals. Over the past few decades, many directed or non-directed C-H acylation processes catalyzed by transition metals have been developed using this strategy. However, in general, their use is limited due to the need for high energy conditions such as high temperature, ultraviolet irradiation, or stoichiometric toxic reagents or oxidants. In recent years, visible light photocatalysis has become an alternative strategy to traditional synthetic methods for structural frameworks that are difficult to synthesize, and Photocatalysts (PCs) generate an excited-state photocatalyst (apc) that can function through a Single Electron Transfer (SET) process, acting not only as a single electron oxidant or single electron reductant, but also as an energy donor, activating acceptor molecules through an energy transfer (EnT) process. Thus, the photocatalytic strategy isThe free radical reaction provides a new platform without the need for free radical initiators and stoichiometric amounts of strong redox agents. All these properties make photocatalysis a sustainable alternative from the point of view of radical reactions, an excellent process for the extraction of acyl radicals.

Sulfonyl radicals are typically generated efficiently from various sulfonyl derivatives by Single Electron Transfer (SET) oxidation. The resulting sulfonyl radicals are also highly reactive intermediates. The sulfone-containing backbones with various activities are easy to be converted into corresponding sulfonyl free radicals. Some of which are by means of a photoredox catalyst (e.g. TiO)₂、Bi₂O₃Eosin Y, fac- [ Ir (ppy)₃]、[Ru(bpy)₃]²⁺) And other catalysts such as strong bases, lewis acids, organic catalysts, and transition metal catalysts. Compared with the prior method, the photo-oxidation-reduction catalysis has the advantages of low cost, high efficiency, easy utilization, environmental friendliness and the like.

The series cyclization of free radicals is a method for synthesizing carbocyclic and heterocyclic compounds with high atom economy and step economy, and has wide application in the fields of chemistry and life science. The radical acceptor with unsaturated bond is the key to realize fast, simple and efficient serial cyclization of free radicals. Carbocycles and heterocycles are extremely important scaffolds in organic synthesis; they are widely found in natural products and bioactive compounds. Thus, various synthetic methods are used in the preparation of carbon and heterocyclic molecules, and so far, due to the sustainability of the synthetic process, free radical tandem cyclization can be said to be one of the most valuable tools, and tandem reactions are considered as an effective strategy for constructing high-value and complex cyclic compounds.

Therefore, it is necessary to study methods for synthesizing various indolyltetrahydropyridinedione derivatives by radical tandem reaction.

Disclosure of Invention

In view of the above, an object of the present invention is to provide a method for preparing indolopyridyl-tetrahydropyridinedione and derivatives thereof by photo-initiated radical tandem reaction; the invention also aims to provide a product prepared by the method for preparing the indolopyridyl-tetrahydropyridine diketone and the derivative thereof by photoinitiating a free radical series reaction.

In order to achieve the purpose, the invention provides the following technical scheme:

1. a method for preparing indolopyridyl tetrahdione and derivatives thereof by photoinitiated radical series reaction, wherein the reaction formula of the method is as follows:

wherein R is¹is-CH₃or-CH₂C₆H₅A group; r²is-CH₃、

Any one of the groups;

R³is composed of

-CF₃or-C₁₀F₂₁Any one of the groups;

the additive is any one of 2, 6-dimethyl pyridine, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylene Diamine (DABCO), triethylamine or potassium acetate;

the photocatalyst is a planar tris (2-phenylpyridine) iridium (fac-Ir (ppy)₃)。

Preferably, the method specifically comprises the following steps: adding a photocatalyst and an additive into an indole derivative II and an acyl chloride organic solvent, irradiating by blue light under the argon atmosphere (argon balloon) for reaction, concentrating and purifying to obtain the indolylpentahydropyridinedione and the derivative thereof.

More preferably, the molar ratio of the indole derivative to the acyl chloride is 1: 1-5.

Further preferably, the organic solvent is any one of tetrahydrofuran, toluene, DMSO, acetone, ethyl acetate, acetonitrile, dichloromethane, or N, N-dimethylformamide.

More preferably, the mol ratio of the indole derivative to the additive is 1: 0.5-2.5; the mol ratio of the indole derivative to the photocatalyst is 1: 0.5-3.0%.

Further preferably, the blue light irradiation is specifically: irradiating for 4-24 h under the blue light with the power of 9-40W.

Further preferably, the purification specifically comprises: and purifying the concentrated solid by adopting a column chromatography method, wherein a mixed solvent formed by petroleum ether and ethyl acetate in a volume ratio of 5: 1-1: 2 is used as an eluent in the purification process.

2. Indolopyridyl-tetrahydropyridinediones and derivatives thereof prepared according to the above preparation process.

Preferably, the structure of the indolopyridyl tetralone and the derivatives thereof is shown in the following I-1-I-51:

the invention has the beneficial effects that: the invention discloses a method for preparing indolyltetrahydropyridinedione and derivatives thereof by photoinitiated free radical series reaction, which mainly comprises the step of reacting indole derivatives and any one of acyl chloride or sulfonyl chloride in the presence of alkali in the presence of a facial type tri (2-phenylpyridine) iridium (fac-Ir (ppy)₃) The indole tetrahydropyridine dione and the derivative thereof are obtained by carrying out a light irradiation reaction under the catalysis of the catalyst, and the indole tetrahydropyridine dione and the derivative thereof belong to the generation of a plurality of indole tetrahydropyridine dione derivatives containing ketone and sulfone through a series cyclization reaction catalyzed by light oxidation reduction between a Michael acceptor and a free radical (wherein the free radical is derived from acyl chloride or sulfonyl chloride). The preparation method of the photo-initiated free radical series reaction has wide free radical source(from readily available acyl chloride or sulfonyl chloride), the free radical tandem strategy provides a concise solution for the simple synthesis of various indolopyridyl-tetrahydropyridine dione derivatives, and further application of the simple solution will create more synthetic value in the foreseeable future.

Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention. The objectives and other advantages of the invention may be realized and attained by the means of the instrumentalities and combinations particularly pointed out hereinafter.

Drawings

For the purposes of promoting a better understanding of the objects, aspects and advantages of the invention, reference will now be made to the following detailed description taken in conjunction with the accompanying drawings in which:

FIG. 1 shows the results of fluorescence quenching experiments during mechanism studies;

FIG. 2 shows the experimental results of switching lamps during the mechanism study;

FIG. 3 is a reaction mechanism for preparing an indolyltetrahydropyridinedione.

Detailed Description

The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention. It should be noted that the drawings provided in the following embodiments are only for illustrating the basic idea of the present invention in a schematic way, and the features in the following embodiments and examples may be combined with each other without conflict.

The main reagents and instruments involved in the following examples: benzoyl chloride, benzenesulfonyl chloride, various acid chlorides and sulfonyl chlorides, etc., tris (2-phenylpyridine) -iridium (fac-Ir (ppy)₃) 4-Dimethylaminopyridine (DMAP),2, 6-dimethylpyridine, carbonPotassium, sodium carbonate, sodium bicarbonate, potassium bicarbonate, triethylene Diamine (DABCO), triethylamine, potassium acetate, DMF, toluene, tetrahydrofuran, acetone, ethyl acetate, petroleum ether, dichloromethane (CH)₂Cl₂) Methanol (MeOH), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), deuterated chloroform, a silica gel plate (Qingdao ocean chemical industry Co., Ltd., ocean GF 254), a nuclear magnetic resonance spectrometer (600MHz, TMS as an internal standard, Bruker instruments Co., Ltd.), a high-resolution mass spectrometer (impact II, ESI ion source, Bruker instruments Co., Ltd.), and a melting point tester (WPX-4, Yuce instruments Equipment Co., Ltd.).

Preparation of ketone-and sulfone-containing indolopyridyl-tetrahydropyridinedione derivatives by the following reaction scheme:

wherein R is¹is-CH₃or-CH₂C₆H₅A group; r²is-CH₃、

Any one of the groups; r³Is composed of

-CF₃or-C₁₀F₂₁Any one of the groups.

Example 1

A compound (2,4, 5-trimethy-4- (2-oxo-2-phenylethyl) -4, 5-dihydrazide [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-1 is prepared by the following steps:

(1) 0.2mmol of R¹is-CH₃、R²is-CH₃Indole derivatives ofThe compound (structural formula is II-1), 0.4mmol of 2,6-lutidine and 1.0mmol of acyl chloride³-Cl, wherein R³Is composed of

) Adding into a round-bottom flask with magnetic stirrer, adding into a planar tris (2-phenylpyridine) iridium (fac-Ir (ppy)₃) (3 mol%, relative to the amount of indole derivative added), evacuation and backfilling with argon (three times);

(2) 2mL of degassed dry organic solvent (CH) were injected under argon₂Cl₂) Irradiating the mixture at room temperature under argon atmosphere (argon balloon) by using a blue LED lamp with the power of 9W, and stirring the mixture for reacting for 4 hours to obtain a mixture (monitoring the reaction by adopting thin layer chromatography, and reacting until the solution contains the indole derivative at noon);

(3) after the reaction was complete, 10mL of water was added to the mixture, followed by 10mL of CH₂Cl₂Extracting for three times, combining organic phases, washing with saturated sodium bicarbonate water solution, and then using anhydrous Na₂SO₄Drying gave a crude product which was purified by column chromatography after removal of the solvent in vacuo (using a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1 as eluent) to give 65.5mg of the compound of formula I-1 as a white solid in 91% yield.

¹H NMR(600MHz,DMSO-d₆)δ8.16–8.06(m,1H),7.96(d,J＝7.8Hz,2H),7.64(t,J＝7.4Hz,1H), 7.58–7.53(m,1H),7.51(t,J＝7.6Hz,2H),7.32–7.23(m,2H),4.59(d,J＝19.1Hz,1H),4.16(d,J＝19.1Hz, 1H),3.88(s,3H),3.23(s,3H),1.71(s,3H)。¹³C NMR(151MHz,DMSO-d₆)δ196.7,176.1,161.8,147.4, 138.2,135.2,133.8,128.7,128.0,124.0,122.9,122.2,119.9,110.5,102.8,46.5,43.4,31.9,26.2,25.8。

HRMS(ESI)calcd.for C₂₂H₂₀N₂O₃[M+Na]⁺:383.1366,found 383.1384。

Example 2

A compound (2,4,5-trimethyl-4- (2-oxo-2- (p-tolyl) ethyl) -4, 5-dihydrado-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-2 is prepared by the following steps:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 56.9mg of the compound of the formula I-2 (white solid, yield 76%).

¹H NMR(600MHz,Chloroform-d)δ8.41–8.31(m,1H),7.76(d,J＝8.0Hz,2H),7.34–7.28(m,3H), 7.24(d,J＝8.0Hz,2H),4.34(d,J＝18.0Hz,1H),4.10(d,J＝18.0Hz,1H),3.83(s,3H),3.42(s,3H),2.41(s, 3H),1.77(s,3H)。¹³C NMR(151MHz,Chloroform-d)δ195.0,176.3,162.4,146.7,144.7,138.4,133.2,129.4, 128.1,124.8,123.4,122.6,121.5,109.2,104.5,47.0,44.0,31.9,26.72,26.69,21.6。

HRMS(ESI)calcd.for C₂₃H₂₂N₂O₃[M+Na]⁺:397.1523,found 397.1532。

Example 3

A compound (4- (2- (4- (tert-butyl) phenyl) -2-oxoethyl) -2,4,5-trimethyl-4,5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-3 is prepared by the following steps:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 58.3mg of the compound of the formula I-3 (white solid, yield 70%).

¹H NMR(600MHz,Chloroform-d)δ8.36(dd,J＝5.9,2.5Hz,1H),7.80(d,J＝8.2Hz,2H),7.45(d,J＝ 8.2Hz,2H),7.34–7.28(m,3H),4.35(d,J＝18.0Hz,1H),4.10(d,J＝18.0Hz,1H),3.84(s,3H),3.42(s,3H), 1.77(s,3H),1.34(s,9H)。¹³C NMR(151MHz,Chloroform-d)δ195.1,176.3,162.4,157.6,146.7,138.4, 133.1,125.7,124.8,123.4,122.6,121.5,109.2,104.4,47.0,44.0,35.2,32.0,31.0,26.73,26.69。

HRMS(ESI)calcd.for C₂₆H₂₈N₂O₃[M+Na]⁺:439.1992,found 439.1993。

Example 4

A compound (4- (2- ([1,1' -biphenyl ] -4-yl) -2-oxoethyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-4 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 47.1mg of a compound of the formula I-4 (white solid, yield 54%).

¹H NMR(600MHz,Chloroform-d)δ8.35(d,J＝6.2Hz,1H),7.91(d,J＝8.0Hz,2H),7.64(d,J＝8.0Hz, 2H),7.59(d,J＝7.6Hz,2H),7.46(t,J＝7.5Hz,2H),7.39(t,J＝7.4Hz,1H),7.30(m,3H),4.38(d,J＝17.9Hz, 1H),4.11(d,J＝17.9Hz,1H),3.83(s,3H),3.40(s,3H),1.77(s,3H)。

¹³C NMR(151MHz,Chloroform-d)δ195.0,176.2,162.4,146.6,146.4,139.6,138.5,134.3,129.0,128.6, 128.4,127.4,127.3,124.8,123.5,122.7,121.6,109.2,104.5,47.1,44.0,32.0,26.75,26.73。

HRMS(ESI)calcd.for C₂₈H₂₄N₂O₃[M+Na]⁺:459.1679,found 459.1692。

Example 5

A compound (4- (2- (2-methoxyphenyl) -2-oxoethyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-5 is prepared by the following steps:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 67.9mg of the compound of the formula I-5 (white solid, yield 87%).

¹H NMR(600MHz,Chloroform-d)δ8.36–8.34(m,1H),7.44(m,J＝9.2,5.8,3.7Hz,2H),7.33–7.30 (m,3H),6.95(d,J＝8.3Hz,1H),6.89(t,J＝7.5Hz,1H),4.33(d,J＝18.3Hz,1H),4.22(d,J＝18.5Hz,1H), 3.93(s,3H),3.83(s,3H),3.39(s,3H),1.73(s,3H)。

¹³C NMR(151MHz,Chloroform-d)δ197.1,176.4,162.5,158.7,146.9,138.4,134.2,130.6,126.4,124.8, 123.32,122.6,121.5,120.8,111.5,109.2,104.3,55.7,52.3,44.2,31.9,26.7,26.6。

HRMS(ESI)calcd.for C₂₃H₂₂N₂O₄[M+Na]⁺:413.1472,found 413.1487。

Example 6

A compound (4- (2- (3-methoxyphenyl) -2-oxoethyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-6 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 49.9mg of the compound of the formula I-6 (white solid, yield 64%).

¹H NMR(600MHz,Chloroform-d)δ8.38-8.35(m,1H),7.50(d,J＝7.6Hz,1H),7.36(t,J＝8.0Hz,1H), 7.34–7.28(m,4H),7.12(dd,J＝8.2,2.7Hz,1H),4.35(d,J＝18.1Hz,1H),4.11(d,J＝18.1Hz,1H),3.84(s, 3H),3.78(s,3H),3.43(s,3H),1.78(s,3H)。

¹³C NMR(151MHz,Chloroform-d)δ195.4,176.2,162.4,160.0,146.5,138.4,136.9,129.7,124.8,123.5, 122.7,121.5,120.6,120.5,112.0,109.2,104.5,55.4,47.2,44.0,32.0,26.73,26.71。

HRMS(ESI)calcd.for C₂₃H₂₂N₂O₄[M+H]⁺:391.1652,found 391.1649。

Example 7

A compound (4- (2- (4-methoxyphenyl) -2-oxoethyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-7 is prepared by the following steps:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 69.4mg of the compound of the formula I-7 (white solid, yield 89%).

¹H NMR(600MHz,DMSO-d₆)δ8.17–8.09(m,1H),7.95(d,J＝8.5Hz,2H),7.58–7.51(m,1H),7.32– 7.24(m,2H),7.02(d,J＝8.5Hz,2H),4.56(d,J＝18.9Hz,1H),4.09(d,J＝18.9Hz,1H),3.88(s,3H),3.83(s, 3H),3.25(s,3H),1.71(s,3H)。¹³C NMR(151MHz,DMSO-d₆)δ195.5,176.8,164.1,162.4,148.1,138.7, 130.9,128.7,124.5,123.4,122.7,120.4,114.5,111.0,103.4,56.1,46.7,44.0,32.4,26.7,26.4。

HRMS(ESI)calcd.for C₂₃H₂₂N₂O₄[M+Na]⁺:413.1472,found 413.1485。

Example 8

A compound (4- (2- (4-fluorophenyl) -2-oxoethyl) -2,4,5-trimethy l-4,5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-8 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 60.5mg of a compound of the formula I-8 (white solid, yield 80%).

¹H NMR(600MHz,DMSO-d₆)δ8.16–8.10(m,1H),8.06(dd,J＝8.6,5.5Hz,2H),7.59–7.51(m,1H), 7.35(t,J＝8.7Hz,2H),7.32–7.25(m,2H),4.59(d,J＝19.2Hz,1H),4.17(d,J＝19.2Hz,1H),3.89(s,3H), 3.24(s,3H),1.72(s,3H)。¹³C NMR(151MHz,DMSO-d₆)δ195.9,176.7,166.7,165.0,162.3,147.8,138.7, 132.51,132.50,131.7,131.6,124.5,123.4,122.7,120.4,116.4,116.2,111.1,103.4,47.0,43.9,32.5,26.7,26.4。

HRMS(ESI)calcd.for C₂₂H₁₉FN₂O₃[M+Na]⁺:401.1272,found 401.1278。

Example 9

A compound (4- (2- (4-chlorophenylyl) -2-oxoethyl) -2,4,5-trimethy l-4,5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-9 is prepared by the following steps:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 64.6mg of a compound of the formula I-9 (white solid, yield 82%).

¹H NMR(600MHz,Chloroform-d)δ8.36(dd,J＝5.5,3.2Hz,1H),7.79(d,J＝8.6Hz,2H),7.41(d,J＝ 8.3Hz,2H),7.35–7.29(m,3H),4.34(d,J＝17.9Hz,1H),4.04(d,J＝18.0Hz,1H),3.84(s,3H),3.41(s,3H), 1.78(s,3H)。¹³C NMR(151MHz,Chloroform-d)δ194.3,176.1,162.3,146.3,140.3,138.5,134.0,129.4,129.1, 124.8,123.6,122.7,121.5,109.2,104.5,46.9,43.9,32.0,26.7。

HRMS(ESI)calcd.for C₂₂H₁₉ClN₂O₃[M+Na]⁺:417.0976,found 417.0983。

Example 10

A compound (4- (2- (4-bromophenyl) -2-oxoethyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-10 is prepared by the following steps:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to obtain 71mg of the compound of the formula I-10 (white solid, yield 81%).

¹H NMR(600MHz,Chloroform-d)δ8.40–8.29(m,1H),7.71(d,J＝8.2Hz,2H),7.58(d,J＝8.1Hz,2H), 7.36–7.29(m,3H),4.33(d,J＝18.0Hz,1H),4.03(d,J＝18.0Hz,1H),3.83(s,3H),3.41(s,3H),1.77(s,3H)。

¹³C NMR(151MHz,Chloroform-d)δ194.5,176.1,162.3,146.2,138.5,134.3,132.1,129.5,129.0,124.8, 123.6,122.8,121.5,109.2,104.5,46.92,43.94,32.0,26.7。

HRMS(ESI)calcd.for C₂₂H₁₉BrN₂O₃[M+Na]⁺:461.0471,found 461.0473。

Example 11

A compound (4- (2- (4-iodophenyl) -2-oxoethyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-11 is prepared by the following steps:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 59.3mg of a compound of the formula I-11 (white solid, yield 61%).

¹H NMR(600MHz,Chloroform-d)δ8.34–8.32(m,1H),7.79(d,J＝8.0Hz,2H),7.54(d,J＝8.1Hz,2H), 7.32–7.28(m,3H),4.30(d,J＝18.0Hz,1H),4.00(d,J＝18.0Hz,1H),3.81(s,3H),3.38(s,3H),1.75(s,3H)。

¹³C NMR(151MHz,Chloroform-d)δ194.8,176.0,162.3,146.2,138.4,138.1,134.8,129.3,124.7,123.6, 122.8,121.6,109.2,104.5,101.9,46.9,43.9,32.0,26.7。

HRMS(ESI)calcd.for C₂₂H₁₉IN₂O₃[M+Na]⁺:509.0333,found 509.0340。

Example 12

A compound (4- (2- (3, 5-dichlorphenyl) -2-oxoethyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-12 is prepared by the following steps:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

Was reacted by the same way with the acid chloride of example 1 to prepare 52.2mg of the compound of the formula I-12 (white solid, yield 61%).

¹H NMR(600MHz,Chloroform-d)δ8.38–8.34(m,1H),7.72(d,J＝1.9Hz,2H),7.56(dd,J＝1.9Hz, 1H),7.37-7.30(m,3H),4.32(d,J＝18.2Hz,1H),4.00(d,J＝18.2Hz,1H),3.85(s,3H),3.42(s,3H),1.79(s, 3H)。¹³C NMR(151MHz,Chloroform-d)δ193.2,175.9,162.2,145.8,138.4,137.9,135.9,133.4,126.4,124.7, 123.7,122.8,121.6,109.2,104.6,47.1,43.8,32.0,26.73,26.69。

HRMS(ESI)calcd.for C₂₂H₁₈C_l2N₂O₃[M+Na]⁺:451.0587,found 451.0595。

Example 13

A compound (4- (2- (4-bromo-2-fluorophenyl) -2-oxoethyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-13 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 53.8mg of a compound of the formula I-13 (white solid, yield 59%).

¹H NMR(600MHz,Chloroform-d)δ8.40–8.30(m,1H),7.54(t,J＝8.2Hz,1H),7.38(dd,J＝10.7,1.8 Hz,1H),7.35–7.31(m,4H),4.28(d,J＝18.9Hz,1H),4.12(d,J＝18.9Hz,1H),3.85(s,3H),3.43(s,3H),1.76 (s,3H)。¹³C NMR(151MHz,Chloroform-d)δ192.5(m),176.1,162.4,161.6(m),146.2,138.4,132.0(m), 129.0(m),128.4(m),124.8,123.5,122.9(m),121.6,120.2(m),109.2,104.5,51.7(m),43.8(m),32.0,26.7, 26.6。

HRMS(ESI)calcd.for C₂₂H₁₈BrFN₂O₃[M+H]⁺:457.0558,found 457.0560。

Example 14

A compound (2,4,5-trimethyl-4- (2-oxo-2- (perfluorophenyl) ethyl) -4,5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-14 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

Was reacted by the same way with the acid chloride of example 1 to prepare 78.3mg of the compound of the formula I-14 (white solid, yield 87%).

¹H NMR(600MHz,Chloroform-d)δ8.32–8.30(m,1H),7.35–7.31(m,3H),4.17(d,J＝18.4Hz,1H), 3.91(d,J＝18.5Hz,1H),3.87(s,3H),3.38(s,3H),1.73(s,3H)。¹³C NMR(151MHz,Chloroform-d)δ189.4, 175.4,161.9,145.4(m),144.9,144.1(m),143.7(m),142.3(m),138.53,138.49(m),136.8(m),124.6,123.8, 122.9,121.6,113.3(m),109.3,104.6,52.7,43.9,31.9,26.7,26.5。

HRMS(ESI)calcd.for C₂₂H₁₅F₅N₂O₃[M+Na]⁺:473.0895,found 473.0904。

Example 15

A compound (2,4,5-trimethyl-4- (2-oxo-2- (4- (trifluoromethyl) phenyl) ethyl) -4, 5-dihydo-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-15 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 48mg of the compound of the formula I-15 (white solid, yield 56%).

¹H NMR(600MHz,Chloroform-d)δ8.37–8.35(m,1H),7.95(d,J＝8.1Hz,2H),7.70(d,J＝8.1Hz,2H), 7.35–7.30(m,3H),4.39(d,J＝18.1Hz,1H),4.07(d,J＝18.1Hz,1H),3.85(s,3H),3.40(s,3H),1.80(s,3H)。

¹³C NMR(151MHz,Chloroform-d)δ194.7,176.0,162.2,146.0,138.5,138.2,135.0(m),128.4,125.8(m), 124.7,123.6,122.8,122.4(m),121.6,109.2,104.6,47.2,43.9,32.0,26.7。

HRMS(ESI)calcd.for C₂₃H₁₉F₃N₂O₃[M+Na]⁺:451.1240,found 451.1249。

Example 16

A compound (methyl-4- (2- (2,4, 5-trimethy-1, 3-dioxo-2,3,4,5-tetrahydro-1H-pyrido [4,3-b ] indol-4-yl) acetyl) benzoate) having a structural formula I-16 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

Was reacted by the same way with the acid chloride of example 1 to prepare 38.4mg of the compound of formula I-16 (white solid, yield 46%).

¹H NMR(600MHz,Chloroform-d)δ8.38–8.33(m,1H),8.11(d,J＝8.5Hz,2H),7.92(d,J＝8.5Hz,2H), 7.36–7.31(m,3H),4.40(d,J＝18.0Hz,1H),4.10(d,J＝18.1Hz,1H),3.96(s,3H),3.85(s,3H),3.42(s,3H), 1.80(s,3H)。¹³C NMR(151MHz,Chloroform-d)δ195.0,176.1,166.0,162.2,146.1,138.7,138.4,134.5, 129.9,127.9,124.8,123.6,122.9,121.6,109.2,104.6,52.5,47.3,43.9,32.0,26.7,26.7。

HRMS(ESI)calcd.for C₂₄H₂₂N₂O₅[M+Na]⁺:441.1421,found 441.1427。

Example 17

A compound (4- (2- (6-chloropyridin-3-yl) -2-oxoethyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-17 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 31.6mg of a compound of the formula I-17 (white solid, yield 40%).

¹H NMR(600MHz,Chloroform-d)δ8.91(d,J＝2.5Hz,1H),8.38–8.35(m,1H),8.04(dd,J＝8.4,2.5 Hz,1H),7.41(d,J＝8.4Hz,1H),7.37–7.32(m,3H),4.35(d,J＝18.1Hz,1H),4.02(d,J＝18.1Hz,1H),3.87 (s,3H),3.42(s,3H),1.81(s,3H)。¹³C NMR(151MHz,Chloroform-d)δ193.3,175.9,162.1,156.4,149.5, 145.7,138.5,138.0,130.0,124.8,124.7,123.7,122.9,121.6,109.2,104.6,47.1,43.8,32.0,26.74,26.69。

HRMS(ESI)calcd.for C₂₁H₁₈ClN₃O₃[M+Na]⁺:418.0929,found 418.0938。

Example 18

A compound (2,4,5-trimethyl-4- (2- (naphthalene-2-yl) -2-oxoethyl) -4,5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-18 is prepared by the following steps:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

Was reacted by the same way with the acid chloride of example 1 to prepare 38.4mg of the compound of formula I-18 (white solid, yield 46%).

¹H NMR(600MHz,Chloroform-d)δ8.46(s,1H),8.38(d,J＝7.1Hz,1H),7.97(d,J＝8.1Hz,1H),7.90–7.83(m,3H),7.63(t,J＝7.2Hz,1H),7.58(t,J＝7.2Hz,1H),7.36–7.31(m,2H),7.29(d,J＝7.2Hz,1H),4.53 (d,J＝17.9Hz,1H),4.26(d,J＝17.9Hz,1H),3.86(s,3H),3.43(s,3H),1.83(s,3H)。

¹³C NMR(151MHz,Chloroform-d)δ195.4,176.3,162.4,146.6,138.5,135.8,133.0,132.4,129.9,129.7, 128.9,128.7,127.8,127.0,124.8,123.5,122.7,121.6,109.2,104.7,77.3,47.2,44.1,32.0,26.8,26.7。

HRMS(ESI)calcd.for C₂₆H₂₂N₂O₃[M+Na]⁺:433.1523,found 433.1530。

Example 19

A compound (2,4,5-trimethyl-4- (2- (naphthalene-1-yl) -2-oxoethyl) -4,5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-19 is prepared by the following steps:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 19.7mg of a compound of the formula I-19 (white solid, yield 24%).

¹H NMR(600MHz,Chloroform-d)δ8.26–8.24(m,1H),7.94(d,J＝8.2Hz,1H),7.81(t,J＝7.5Hz,2H), 7.78(d,J＝8.2Hz,1H),7.45(t,J＝7.7Hz,1H),7.40(t,J＝7.5Hz,1H),7.33–7.30(m,2H),7.29–7.26(m, 1H),7.22-7.19(m,J＝8.4,6.8,1.4Hz,1H),4.53(d,J＝17.0Hz,1H),3.97(d,J＝17.1Hz,1H),3.82(s,3H), 3.28(s,3H),1.77(s,3H)。

¹³C NMR(151MHz,Chloroform-d)δ199.9,176.1,162.0,146.0,138.5,134.3,133.7,133.2,129.7,128.2, 128.0,127.6,126.6,125.1,124.7,124.0,123.6,122.7,121.5,109.2,104.5,50.7,44.6,32.0,26.7,26.6。

HRMS(ESI)calcd.for C₂₆H₂₂N₂O₃[M+Na]⁺:433.1523,found 433.1530。

Example 20

A compound (4- (2- (2-chloropyridin-3-yl) -2-oxoethyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-20 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

Was reacted by the same way with the acid chloride of example 1 to prepare 32.4mg of the compound of formula I-20 (white solid, yield 41%).

¹H NMR(600MHz,Chloroform-d)δ8.46(dd,J＝4.7,2.0Hz,1H),8.37–8.34(m,1H),7.57(dd,J＝7.6, 2.0Hz,1H),7.38-7.35(m,2H),7.35–7.32(m,1H),7.23(dd,J＝7.6,4.7Hz,1H),4.35(d,J＝17.9Hz,1H), 4.18(d,J＝17.8Hz,1H),3.88(s,3H),3.39(s,3H),1.78(s,3H)。

¹³C NMR(151MHz,Chloroform-d)δ197.2,175.7,162.1,151.8,147.2,145.4,138.7,138.5,134.0,124.6, 123.8,122.9,122.6,121.6,109.3,104.5,51.0,44.4,32.1,26.7,26.6。

HRMS(ESI)calcd.for C₂₁H₁₈ClN₃O₃[M+Na]⁺:418.0923,found 418.0939。

Example 21

A compound (4- (2- (4-ethylphenyl) -2-oxoethyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-21 is prepared by the following steps:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The remainder of the reactions were carried out according to the method in example 1 to prepare 76.1mg of the compound of formula I-21 (white solid,yield 83%).

¹H NMR(600MHz,Chloroform-d)δ8.36(m,1H),7.78(d,J＝8.0Hz,2H),7.32(m,3H),7.24(d,J＝8.0 Hz,2H),4.35(d,J＝18.0Hz,1H),4.10(d,J＝18.0Hz,1H),3.84(s,3H),3.42(s,3H),2.65(t,J＝7.7Hz,2H), 1.77(s,3H),1.62(t,J＝7.5Hz,2H),1.35–1.27(m,8H),0.90(t,J＝6.9Hz,3H)。

¹³C NMR(151MHz,Chloroform-d)δ195.1,176.3,162.4,149.6,146.7,138.4,133.4,128.8,128.2,124.8, 123.4,122.6,121.6,109.2,104.5,47.0,44.0,36.0,31.9,31.7,31.0,29.2,29.1,26.72,26.69,22.6,14.0。

HRMS(ESI)calcd.for C₂₉H₃₄N₂O₃[M+Na]⁺:481.2462,found 481.2468。

Example 22

A compound (2,4,5-trimethyl-4- (2-oxo-2- (thiophen-2-yl) ethyl) -4,5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-22 is prepared by the following steps:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 41.7mg of the compound of the formula I-22 (white solid, yield 57%).

¹H NMR(600MHz,DMSO-d₆)δ8.17(d,J＝3.8Hz,1H),8.14–8.08(m,1H),8.01(d,J＝4.9Hz,1H), 7.57(d,J＝7.1Hz,1H),7.28(m,3H),4.53(d,J＝18.7Hz,1H),4.09(d,J＝18.6Hz,1H),3.92(s,3H),3.24(s, 3H),1.72(s,3H)。¹³C NMR(151MHz,DMSO-d₆)δ190.1,176.5,162.2,147.5,142.7,138.7,136.3,134.7,129.4,124.4,123.5,122.7,120.5,111.1,103.4,47.1,44.0,32.5,26.8,26.3。

HRMS(ESI)calcd.for C₂₀H₁₈N₂O₃S[M+Na]⁺:389.0930,found 389.0936。

Example 23

A compound (4- (2- (furan-2-yl) -2-oxoethyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-23 is prepared by the following steps:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 12.6mg of a compound of the formula I-23 (white solid, yield 18%).

¹H NMR(600MHz,Chloroform-d)δ8.35–8.33(m,1H),7.57(dd,J＝1.8Hz,1H),7.32(m,3H),7.13(d, J＝3.6Hz,1H),6.53(dd,J＝3.7,1.8Hz,1H),4.16(d,J＝17.9Hz,1H),4.02(d,J＝18.0Hz,1H),3.88(s,3H), 3.43(s,3H),1.78(s,3H)。¹³C NMR(151MHz,Chloroform-d)δ184.5,176.0,162.3,151.9,146.6,146.0,

138.5,124.8,123.5,122.7,121.6,117.5,112.7,109.2,104.5,46.6,43.7,32.0,26.7,26.6。

HRMS(ESI)calcd.for C₂₀H₁₈N₂O₄[M+Na]⁺:373.1159,found 373.1171。

Example 24

A compound (4- (2- (4-butylphenyl) -2-oxoethyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-24 is prepared by the following steps:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The remainder was reacted as in example 1 to give 724mg of the compound of formula I-24 (white solid, 87% yield).

¹H NMR(600MHz,Chloroform-d)δ8.38–8.35(m,1H),7.78(d,J＝8.0Hz,2H),7.34–7.28(m,3H), 7.24(d,J＝7.9Hz,2H),4.34(d,J＝18.0Hz,1H),4.10(d,J＝18.0Hz,1H),3.83(s,3H),3.42(s,3H),2.66(t,J ＝7.8Hz,2H),1.76(s,3H),1.61(m,2H),1.36(m,2H),0.94(t,J＝7.4Hz,3H)。

¹³C NMR(151MHz,Chloroform-d)δ195.1,176.3,162.4,149.6,146.7,138.5,133.4,128.8,128.2,124.8, 123.4,122.6,121.5,109.2,104.4,47.0,44.0,35.7,33.1,31.9,26.70,26.68,22.3,13.8。

HRMS(ESI)calcd.for C₂₆H₂₈N₂O₃[M+Na]⁺:439.1992,found 439.1996。

Example 25

Preparation of the Compound of formula I-25 (4- ((ethylsulfonyl) methyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido)

[4,3-b ] indole-1,3(2H) -dione), prepared as follows:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 42.5mg of a compound of the formula I-25 (white solid, yield 61%).

¹H NMR(600MHz,Chloroform-d)δ8.34(d,J＝7.6Hz,1H),7.41–7.33(m,3H),4.41(d,J＝14.3Hz, 1H),3.94(s,3H),3.81(d,J＝14.2Hz,1H),3.43(s,3H),2.88–2.83(m,2H),1.74(s,3H),1.34–1.30(t,J＝5.76, 3H)。¹³C NMR(151MHz,Chloroform-d)δ174.3,161.6,142.9,138.7,124.5,124.0,122.9,121.7,109.5,104.3, 57.9,49.4,43.4,32.1,27.5,26.9,6.2。

HRMS(ESI)calcd.for C₁₇H₂₀N₂O₄S[M+Na]⁺:371.1036,found 371.1045。

Example 26

A compound (4- ((isobutylsulfonyl) methyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-26 is prepared by the following steps:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 56.4mg of the compound of the formula I-26 (white solid, yield 75%).

¹H NMR(600MHz,Chloroform-d)δ8.34(d,J＝7.7Hz,1H),7.36(m,3H),4.39(d,J＝14.3Hz,1H),3.94 (s,3H),3.82(d,J＝14.3Hz,1H),3.43(s,3H),2.78–2.71(m,2H),2.27(m,1H),1.74(s,3H),1.03(dd,J＝9.1, 6.7Hz,6H)。

¹³C NMR(151MHz,Chloroform-d)δ174.4,161.6,142.9,138.7,124.5,124.0,122.9,121.7,109.5,104.3, 62.6,59.8,43.4,32.1,27.4,26.9,23.5,22.7,22.6。

HRMS(ESI)calcd.for C₁₉H₂₄N₂O₄S[M+Na]⁺:399.1349,found 399.1358。

Example 27

A compound (2,4,5-trimethyl-4- ((phenylethanylsulfonyl) methyl) -4, 5-dihydrio-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-27 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

With the remainder being as per the practiceThe reaction was carried out in the same manner as in example 1 to obtain 66.2mg of the compound of the formula I-27 (white solid, yield 78%).

¹H NMR(600MHz,Chloroform-d)δ8.35(m,1H),7.39–7.35(m,3H),7.32(m,2H),7.28(m,1H),7.14 (d,J＝7.2Hz,2H),4.33(d,J＝14.4Hz,1H),3.90(s,3H),3.67(d,J＝14.4Hz,1H),3.42(s,3H),3.11–3.03(m, 4H),1.71(s,3H)。¹³C NMR(151MHz,Chloroform-d)δ174.3,161.6,142.8,138.7,137.2,128.9,128.4,127.2, 124.5,124.1,122.9,121.7,109.6,104.4,59.1,56.4,43.4,32.1,27.8,27.3,26.9。

HRMS(ESI)calcd.for C₂₃H₂₄N₂O₄S[M+Na]⁺:447.1349,found 447.1357。

Example 28

A compound (2,4,5-trimethyl-4- ((octyclfonyl) methyl) -4,5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-28 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to obtain 70.9mg of a compound of the formula I-28 (white solid, yield 82%).

¹H NMR(600MHz,Chloroform-d)δ8.33(d,J＝7.6Hz,1H),7.41–7.33(m,3H),4.40(d,J＝14.3Hz, 1H),3.94(s,3H),3.82(d,J＝14.3Hz,1H),3.43(s,3H),2.81(dd,J＝9.8,6.3Hz,2H),1.77–1.70(m,6H),1.38 –1.25(m,9H),0.89(t,J＝7.1Hz,3H)。¹³C NMR(151MHz,Chloroform-d)δ174.3,161.6,142.9,138.7,124.5, 124.0,122.9,121.7,109.5,104.3,58.6,55.1,43.5,32.2,31.6,28.88,28.85,28.3,27.4,26.9,22.5,21.5,14.0。

HRMS(ESI)calcd.for C₂₃H₃₂N₂O₄S[M+Na]⁺:455.1975,found 455.1969。

Example 29

A compound (4- ((cyclopropysulfonyl) methyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-29 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 46.8mg of a compound of the formula I-29 (white solid, yield 65%).

¹H NMR(600MHz,Chloroform-d)δ8.34(d,J＝7.4Hz,1H),7.41–7.34(m,3H),4.53(d,J＝14.7Hz, 1H),3.95(s,3H),3.91(d,J＝14.7Hz,1H),3.42(s,3H),2.14(m,1H),1.77(s,3H),1.10–1.06(m,2H),0.92– 0.88(m,2H)。¹³C NMR(151MHz,Chloroform-d)δ174.3,161.6,143.0,138.7,124.5,124.1,122.9,121.7, 109.5,104.3,60.1,43.7,32.2,30.8,27.5,26.9,5.1,4.9。

HRMS(ESI)calcd.for C₁₈H₂₀N₂O₄S[M+Na]⁺:383.1036,found 383.1042。

Example 30

A compound (4- ((cyclohexylsulfonyl) methyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-30 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

Was reacted by the same way as in example 1 to prepare 57.9mg of a compound of the formula I-30 (white solid)Yield 72%).

¹H NMR(600MHz,Chloroform-d)δ8.33(d,J＝6.9Hz,1H),7.40–7.31(m,3H),4.41(d,J＝14.0Hz, 1H),3.93(s,3H),3.72(d,J＝14.0Hz,1H),3.42(s,3H),2.71(m,1H),2.12(t,J＝11.8Hz,2H),1.91(d,J＝12.7 Hz,2H),1.73(s,3H),1.50–1.39(m,2H),1.25(m,4H)。

¹³C NMR(151MHz,Chloroform-d)δ174.5,161.7,143.1,138.7,124.6,123.9,122.8,121.7,109.5,104.3,63.1, 55.3,43.1,32.1,27.5,26.9,25.2,25.0,24.94,24.92,24.5。

HRMS(ESI)calcd.for C₂₁H₂₆N₂O₄S[M+Na]⁺:425.1505,found 425.1514。

Example 31

Preparation of the Compound of formula I-31 (4- (((((4S) -7, 7-dimethyl-2-oxocylic [2.2.1] heptan-1-yl) methyl)

sulfo) methyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) prepared as follows:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 72.4mg of a compound of the formula I-31 (white solid, yield 77%).

¹H NMR(600MHz,Chloroform-d)δ8.33(m,1H),7.46–7.30(m,3H),4.46(dd,J＝14.6,8.0Hz,1H), 4.17(d,J＝14.7Hz,1H),3.96(s,1H),3.95(s,2H),3.43(s,1H),3.40(s,2H),3.11(d,J＝14.9Hz,1H),2.36–

2.30(m,1H),2.21(m,1H),2.06(t,J＝4.7Hz,1H),2.00–1.91(m,2H),1.78(d,J＝13.2Hz,4H),1.43(m,1H), 0.93(s,1H),0.88(s,1H),0.81(s,2H),0.57(s,2H)。

¹³C NMR(151MHz,Chloroform-d)δ215.8,215.7,174.7,174.1,161.74,161.72,143.3,142.7,138.8, 138.7,124.5,124.1,123.8,122.9,122.7,121.8,121.6,109.5,104.6,61.9,61.6,59.4,58.7,54.4,52.2,48.9,48.7, 43.5,43.3,42.7,42.58,42.57,42.4,32.2,32.1,27.4,27.1,27.0,26.94,26.88,25.9,24.5,19.7,19.4,19.3,19.2。

HRMS(ESI)calcd.for C₂₅H₃₀N₂O₅S[M+Na]⁺:493.1768,found 493.1775。

Example 32

A compound (2,4,5-trimethyl-4- ((phenylsulfonyl) methyl) -4,5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-32 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

Was reacted by the same way with the acid chloride of example 1 to prepare 62mg of the compound of formula I-32 (white solid, yield 78%).

¹H NMR(600MHz,Chloroform-d)δ8.36–8.34(m,1H),7.46(m,J＝15.5,7.9Hz,3H),7.38–7.36(m, 2H),7.25–7.19(m,3H),4.56(d,J＝15.1Hz,1H),3.99(d,J＝15.1Hz,1H),3.62(s,3H),3.24(s,3H),1.71(s, 3H)。¹³C NMR(151MHz,Chloroform-d)δ173.7,161.5,142.0,138.5,138.2,133.8,128.9,128.0,124.3,124.1, 123.0,121.7,109.5,104.7,62.5,43.8,31.9,27.3,26.8。

HRMS(ESI)calcd.for C₂₇H₃₀N₂O₄S[M+H]⁺:397.1217,found 397.1216。

Example 33

A compound (4- (((4-cyclohexenylphenyl) sulfonyl) methyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-33 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 56.4mg of a compound of the formula I-33 (white solid, yield 59%).

¹H NMR(600MHz,Chloroform-d)δ8.39–8.33(m,1H),7.40–7.36(m,2H),7.33(d,J＝8.3Hz,2H), 7.24–7.20(m,1H),7.07(d,J＝8.0Hz,2H),4.58(d,J＝15.1Hz,1H),3.97(d,J＝15.1Hz,1H),3.64(s,3H), 3.19(s,3H),2.48(m,1H),1.90–1.86(m,2H),1.83–1.77(m,3H),1.71(s,3H),1.45–1.32(m,5H)。

¹³C NMR(151MHz,Chloroform-d)δ173.7,161.4,154.9,142.2,138.6,135.4,128.3,127.4,124.3,124.1, 122.9,121.7,109.5,104.7,62.5,44.5,43.8,34.0,33.9,31.9,27.5,26.8,26.58,26.56,25.9。

HRMS(ESI)calcd.for C₂₇H₃₀N₂O₄S[M+Na]⁺:501.1818,found 501.1827。

Example 34

A compound (2,4, 5-trimethy-4- (((4-phenoxyphenyl) sulfonyl) methyl) -4, 5-dihydrio-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-34 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 53.7mg of a compound of the formula I-34 (white solid, yield 55%).

¹H NMR(600MHz,Chloroform-d)δ8.33(d,J＝7.6Hz,1H),7.45(t,J＝7.8Hz,2H),7.38(m,4H),7.29 (m,2H),7.04(d,J＝7.9Hz,2H),6.76(d,J＝8.8Hz,2H),4.59(d,J＝15.1Hz,1H),3.98(d,J＝15.0Hz,1H), 3.75(s,3H),3.26(s,3H),1.73(s,3H)。

¹³C NMR(151MHz,Chloroform-d)δ173.7,162.8,161.4,154.4,142.1,138.6,131.3,130.5,130.2,125.4, 124.3,124.2,123.0,121.7,120.6,116.9,109.4,104.7,62.6,43.9,32.0,27.5,26.8。

HRMS(ESI)calcd.for C₂₇H₂₄N₂O₅S[M+Na]⁺:511.1298,found 511.1308。

Example 35

A compound represented by the formula I-35 (N- (4- (((2,4,5-trimethyl-1,3-dioxo-2,3,4,5-tetrahydro-1H-pyrido [4,3-b ] indol-4-yl) methyl) sulfonyl) phenyl) acetamide) was prepared as follows:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 65.3mg of a compound of the formula I-35 (white solid, yield 72%).

¹H NMR(600MHz,DMSO-d₆)δ10.25(s,1H),8.13–8.10(m,1H),7.44(d,J＝8.5Hz,2H),7.42–7.39 (m,1H),7.30(dd,J＝6.1,3.1Hz,2H),7.28(d,J＝8.8Hz,2H),4.67(d,J＝15.5Hz,1H),4.18(d,J＝15.5Hz, 1H),3.64(s,3H),3.13(s,3H),2.07(s,3H),1.66(s,3H)。

¹³C NMR(151MHz,DMSO-d₆)δ174.4,169.5,161.6,144.6,143.4,138.8,132.1,128.9,124.1,123.9, 122.8,120.6,118.6,110.9,103.7,62.1,43.8,32.3,26.9,26.6,24.6。

HRMS(ESI)calcd.for C₂₃H₂₃N₃O₅S[M+Na]⁺:476.1251,found 476.1241。

Example 36

A compound of formula I-36 (2,4,5-trimethyl-4- (((perfluorophenyl) sulfonyl) methyl) -4,5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) was prepared as follows:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 43.7mg of a compound of the formula I-36 (white solid, yield 45%).

¹H NMR(600MHz,Chloroform-d)δ8.33(dd,J＝6.9,2.0Hz,1H),7.42–7.36(m,2H),7.23–7.21(m, 1H),4.49(d,J＝15.0Hz,1H),4.22(d,J＝15.0Hz,1H),3.84(s,3H),3.43(s,3H),1.90(s,3H)。

¹³C NMR(151MHz,Chloroform-d)δ172.9,161.1,145.4(m),143.7(m),140.7,138.3,136.6(m),124.9, 123.7,123.6,122.1,113.9(m),108.6,105.5,64.4,43.5,32.0,27.0,26.3。

HRMS(ESI)calcd.for C₂₁H₁₅F₅N₂O₄S[M+Na]⁺:509.0565,found 509.0565。

Example 37

A compound (2,4,5-trimethyl-4- (((5,6,7, 8-tetrahydronaphthalene-2-yl) sulfo) methyl) -4,5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-37 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 67.5mg of a compound of the formula I-37 (white solid, yield 75%).

¹H NMR(600MHz,Chloroform-d)δ8.37–8.32(m,1H),7.38–7.33(m,2H),7.25(m,1H),7.20–7.16 (m,1H),6.96(d,J＝8.1Hz,1H),6.90(d,J＝2.2Hz,1H),4.53(d,J＝15.2Hz,1H),3.98(d,J＝15.2Hz,1H), 3.59(s,3H),3.24(s,3H),2.67(t,J＝5.9Hz,2H),2.52–2.46(m,1H),2.10(m,1H),1.69(s,7H)。

¹³C NMR(151MHz,Chloroform-d)δ173.7,161.5,144.3,142.0,138.59,138.56,134.7,129.5,128.8, 124.7,124.3,124.1,122.9,121.7,109.3,104.8,62.5,43.8,31.9,29.5,28.6,27.3,26.7,22.4,22.3。

HRMS(ESI)calcd.for C₂₅H₂₆N₂O₄S[M+Na]⁺:473.1505,found 473.1505。

Example 38

A compound (4- (((2,3-dihydrobenzofuran-5-yl) sulfonyl) methyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-38 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to obtain 74.5mg of a compound of the formula I-38 (white solid, yield 85%).

¹H NMR(600MHz,Chloroform-d)δ8.37–8.35(m,1H),7.42(d,J＝8.2Hz,1H),7.38–7.36(m,2H), 7.22-7.20(m,1H),6.86(s,1H),6.69(d,J＝8.4Hz,1H),4.57–4.51(m,2H),4.42–4.35(m,1H),3.98(d,J＝ 15.2Hz,1H),3.56(s,3H),3.29(s,3H),2.89-2.84(m,1H),2.35-2.28(m,1H),1.69(s,3H)。

¹³C NMR(151MHz,Chloroform-d)δ173.8,164.6,161.6,142.1,138.6,129.7,129.2,128.6,125.5,124.3, 124.1,122.9,121.7,109.38,109.36,104.8,72.6,62.9,43.9,31.9,28.1,27.2,26.8。

HRMS(ESI)calcd.for C₂₃H₂₂N₂O₅S[M+Na]⁺:461.1142,found 461.1147。

Example 39

A compound (2,4, 5-trimethy-4- (((2-oxo-2H-chromen-6-yl) sulfonyl) methyl) -4,5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-39 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

Was otherwise reacted according to the method of example 1 to prepare 78mg of the compound of formula I-39 (white solid, yield 84%).

¹H NMR(600MHz,Chloroform-d)δ8.33(m,1H),7.79–7.74(m,1H),7.33(m,1H),7.29(m,2H),7.20 (s,1H),7.07–7.00(m,2H),6.28(m,1H),4.59(d,J＝15.3Hz,1H),4.00(d,J＝15.3Hz,1H),3.52(s,3H),3.29 (s,3H),1.74(s,3H)。¹³C NMR(151MHz,Chloroform-d)δ173.5,161.4,158.7,156.8,141.7,141.4,138.3, 134.1,130.3,128.8,124.7,124.1,123.5,121.7,118.7,118.1,117.6,109.2,105.0,62.7,43.8,31.9,27.0,26.9。

HRMS(ESI)calcd.for C₂₄H₂₀N₂O₆S[M+Na]⁺:487.0934,found 487.0940。

Example 40

A compound (4- (((5- (dimethylamino) naphthalene-1-yl) sulfonyl) methyl) -2,4,5-trimethyl-4,5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-40 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The remainder being as in example 1The reaction was carried out to prepare 47mg of the compound of the formula I-40 (white solid, yield 48%).

¹H NMR(600MHz,Chloroform-d)δ8.34(d,J＝7.8Hz,1H),8.31(d,J＝8.6Hz,1H),8.23(d,J＝8.4Hz, 1H),7.68–7.64(m,1H),7.46(dd,J＝7.2,1.3Hz,1H),7.36(t,J＝7.2Hz,1H),7.32-7.29(m,1H),7.23(d,J＝ 7.5Hz,1H),6.92(d,J＝8.2Hz,1H),6.83–6.79(t,1H),4.68(d,J＝15.1Hz,1H),4.22(d,J＝15.1Hz,1H), 3.27(s,3H),3.15(s,3H),2.91(s,6H),1.70(s,3H)。

¹³C NMR(151MHz,Chloroform-d)δ173.7,161.7,152.4,141.7,138.3,132.8,131.2,130.5,129.8,129.2, 129.0,124.2,123.9,122.9,122.8,121.7,117.8,115.3,109.1,105.0,61.9,45.4,43.8,31.3,26.83,26.78。

HRMS(ESI)calcd.for C₂₇H₂₇N₃O₄S[M+Na]⁺:512.1614,found 512.1615。

EXAMPLE 41

The compound (2,4,5-trimethyl-4- ((quinolin-5-ylsulfonyl) methyl) -4,5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with the structural formula I-41 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 37.6mg of a compound of the formula I-41 (white solid, yield 42%).

¹H NMR(600MHz,Chloroform-d)δ9.34(s,1H),8.80(d,J＝6.0Hz,1H),8.43(d,J＝6.0Hz,1H),8.32 (d,J＝7.7Hz,1H),7.91(d,J＝8.1Hz,1H),7.71(d,J＝7.4Hz,1H),7.39-7.32(m,2H),7.06(t,J＝7.8Hz,1H), 6.96(d,J＝8.1Hz,1H),4.68(d,J＝15.1Hz,1H),4.14(d,J＝15.1Hz,1H),3.27(s,3H),3.23(s,3H),1.73(s, 3H)。¹³C NMR(151MHz,Chloroform-d)δ173.4,161.4,153.4,145.7,141.3,138.3,134.6,134.2,132.0,131.4, 128.3,125.6,124.2,124.1,123.1,121.8,116.3,109.2,105.1,62.1,43.7,31.6,26.9,26.8。

HRMS(ESI)calcd.for C₂₄H₂₁N₃O₄S[M+H]⁺:448.1326,found 448.1327。

Example 42

A compound (4- ((benzo [ c ] [1,2,5] oxadiazinyl-4-ylsulfonyl) methyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-42 is prepared by the following method:

r in example 1³Is composed of

By replacement of the acid chloride of (A) with R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 54.3mg of a compound of the formula I-42 (white solid, yield 62%).

¹H NMR(600MHz,Chloroform-d)δ8.25(d,J＝7.7Hz,1H),7.56(d,J＝9.0Hz,1H),7.35(d,J＝6.7Hz, 1H),7.34–7.30(m,1H),7.30-7.27(m,1H),6.79(d,J＝8.1Hz,1H),6.75(dd,J＝9.0,6.7Hz,1H),4.53(s,2H), 3.41(s,3H),3.24(s,3H),1.85(s,3H)。¹³C NMR(151MHz,Chloroform-d)δ173.2,161.5,148.8,144.1,141.1, 137.9,134.5,129.0,125.6,124.5,123.8,123.3,121.8,120.8,109.1,105.6,62.0,43.4,31.5,27.0,25.9。

HRMS(ESI)calcd.for C₂₁H₁₈N₄O₅S[M+Na]⁺:461.0890,found 461.0899。

Example 43

A compound (5-benzyl-2,4-dimethyl-4- (2-oxo-2-phenylethyl) -4,5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-43 is prepared by the following steps:

the indole derivative (structural formula II-1) in example 1 was replaced with R³Is an indole derivative (structural formula II-1), and the rest is reacted according to the method in example 1 to prepare67.5mg of the compound of formula I-43 was obtained (white solid, 80% yield).

¹H NMR(600MHz,Chloroform-d)δ8.46(d,J＝8.0Hz,1H),7.43(m,3H),7.36(t,J＝7.5Hz,1H),7.24 (m,3H),7.15(d,J＝8.3Hz,1H),6.89(t,J＝7.6Hz,2H),6.77(t,J＝7.5Hz,1H),6.72(d,J＝7.7Hz,2H),5.62 (d,J＝17.7Hz,1H),5.49(d,J＝17.7Hz,1H),4.11(d,J＝18.3Hz,1H),3.81(s,1H),3.46(s,3H),1.78(s, 3H)。¹³C NMR(151MHz,Chloroform-d)δ195.3,176.5,162.6,146.6,138.4,135.2,135.0,133.0,129.0,128.1, 127.64,127.55,124.93,124.87,123.8,122.9,121.7,109.8,105.3,48.4,47.7,43.7,27.0,26.7。

HRMS(ESI)calcd.for C₂₇H₂₂N₂O₃[M+Na]⁺:459.1679,found 459.1686。

Example 44

A compound (2-cyclopropyl-4,5-dimethyl-4- (2-oxo-2-phenylethyl) -4,5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-44 is prepared by the following steps:

the indole derivative (structural formula II-1) in example 1 was replaced with R³As an indole derivative (structural formula II-3), the reaction was carried out in the same manner as in example 1 to obtain 50.6mg of a compound of structural formula I-44 (white solid, yield 68%).

¹H NMR(600MHz,Chloroform-d)δ8.36(m,1H),7.87–7.84(m,2H),7.57(t,J＝7.4Hz,1H),7.43(t,J ＝7.7Hz,2H),7.31(m,2H),7.27(d,J＝6.6Hz,1H),4.33(d,J＝18.0Hz,1H),4.08(d,J＝18.0Hz,1H),3.81(s, 3H),2.78(m,1H),1.73(s,3H),1.17(m,2H),0.86–0.81(m,1H),0.75(m,1H).

¹³C NMR(151MHz,Chloroform-d)δ195.4,177.2,163.1,146.3,138.4,135.7,133.7,128.7,128.0,124.8, 123.4,122.7,121.6,109.2,104.9,46.7,44.2,31.9,26.4,24.0,8.6,8.2.

HRMS(ESI)calcd.for C₂₃H₂₀N₂O₃[M+Na]⁺:409.1523,found 409.1521。

Example 45

A compound (2- (cyclobutylmethyl) -4,5-dimethyl-4- (2-oxo-2-phenylethyl) -4,5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula of I-45 is prepared by the following steps:

the indole derivative of the formula II-1 of example 1 was replaced with an indole derivative of the formula II-4, and the reaction was carried out in the same manner as in example 1 to obtain 49.6mg of the compound of the formula I-45 (white solid, yield 62%).

¹H NMR(600MHz,Chloroform-d)δ8.37(d,J＝8.0Hz,1H),7.88(d,J＝7.3Hz,2H),7.58(t,J＝7.4Hz, 1H),7.45(t,J＝7.7Hz,2H),7.33(m,2H),7.29(m,1H),4.38(d,J＝18.0Hz,1H),4.13–4.06(m,3H),3.82(s, 3H),2.79(m,1H),2.06–1.98(m,2H),1.86(m,4H),1.76(s,3H)。¹³C NMR(151MHz,Chloroform-d)δ

195.2,176.2,162.4,146.5,138.5,135.8,133.6,128.7,128.0,124.9,123.4,122.6,121.6,109.1,104.5,46.9,44.5, 44.0,34.8,31.9,26.9,26.4,26.4,18.4。

HRMS(ESI)calcd.for C₂₆H₂₆N₂O₃[M+H]⁺:415.2016,found 415.2017。

Example 46

A compound (4,5-dimethyl-4- (2-oxo-2-phenylethyl) -2- (((R) -tetrahydrofuran-2-yl) methyl) -4,5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-46 is prepared by the following method:

the indole derivative of the formula II-1 of example 1 was replaced with an indole derivative of the formula II-5, and the reaction was carried out in the same manner as in example 1 to obtain 57.4mg of the compound of the formula I-46 (white solid, yield 69%).

¹H NMR(600MHz,Chloroform-d)δ8.36(m,1H),7.88(t,J＝6.6Hz,2H),7.58(t,J＝7.4Hz,1H),7.45(t, J＝7.6Hz,2H),7.35–7.27(m,3H),4.42–4.21(m,3H),4.15–4.03(m,2H),3.93(m,1H),3.82(d,J＝4.6Hz, 3H),3.78–3.73(m,1H),2.07–1.95(m,2H),1.90–1.85(m,1H),1.79(d,J＝2.6Hz,3H),1.73(m,1H)。

¹³C NMR(151MHz,Chloroform-d)δ195.4,195.3,176.2,176.1,162.2,146.7,146.5,138.5,135.72,

135.70,133.7,128.7,128.0,124.94,124.91,123.43,123.41,122.65,122.64,121.7,121.6,109.1,104.5,104.4, 76.6,76.1,67.8,67.7,46.84,46.81,44.1,43.0,43.1,42.8,31.9,29.27,29.25,26.9,26.8,25.42,25.39。

HRMS(ESI)calcd.for C₂₅H₂₄N₂O₄[M+H]⁺:431.1965,found 431.1965。

Example 47

A compound ((4S) -2- (((1R,4aS) -7-isoproyl-1, 4a-dimethyl-1,2,3,4,4a,9,10,10 a-octahydrophenanthren-1-yl) methyl) -4,5-dimethyl-4- (2-oxo-2-phenylethyl) -4,5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) having a structural formula I-47 is prepared by the following method:

the indole derivative of the formula II-1 of example 1 was replaced with an indole derivative of the formula II-6, and the reaction was carried out in the same manner as in example 1 to prepare 70mg of the compound of the formula I-47 as a white solid in a yield of 57%.

¹H NMR(400MHz,Chloroform-d)δ8.35(m,1H),7.87–7.71(m,2H),7.56–7.49(m,1H),7.44–7.34 (m,2H),7.32–7.24(m,3H),7.12(t,J＝7.3Hz,1H),6.97–6.80(m,2H),4.35(m,1H),4.03(dd,J＝18.2,6.0 Hz,1H),3.78(s,1H),3.76(s,1H),2.95(m,2H),2.81(m,1H),2.33–2.18(m,2H),1.77(m,J＝11.7,6.2,4.9Hz, 2H),1.69(s,2H),1.65–1.61(m,1H),1.59–1.53(m,2H),1.51(m,2H),1.42(m,1H),1.27(m,3H),1.23(m, 2H),1.21(s,4H),1.19(d,J＝6.6Hz,3H),1.02(s,3H)。¹³C NMR(101MHz,Chloroform-d)δ195.2,

177.1,163.0,147.7,147.6,145.4,138.5,135.7,135.6,135.1,135.0,133.6,133.5,128.7,128.7,128.0,127.9,

126.9,125.0,123.9,123.8,123.6,123.5,123.4,122.6,122.6,121.7,109.1,109.1,104.7,44.3,44.2,39.9,39.8, 38.4,38.2,37.8,37.8,37.5,33.5,33.4,31.9,30.5,30.4,29.7,27.3,27.2,26.1,25.9,24.0,23.9,23.9,19.8,19.7,

18.9,18.8,18.7,18.6,14.1。

HRMS(ESI)calcd.for C₄₁H₄₆N₂O₃[M+H]⁺:615.3581,found 615.3576。

Example 48

The influence of different factors in the photoinitiated free radical series reaction on the product is researched:

1. effect of the photocatalyst class on the preparation of Indolo-tetrahydropyridinediones (compounds of formula I-1):

the photoinitiator of example 1 was a tris (2-phenylpyridine) iridium (fac-Ir (ppy)₃) The reaction conditions were the same as in example 1 except that tris (2,2' -bipyridine) ruthenium bis (hexafluorophosphate) salt or acid red 87 was used instead, and the results of preparing indolyltetrahydropyridinedione (compound of formula I-1) are shown in Table 1.

TABLE 1 yield of indolo-tetrahydropyridinedione (compound of formula I-1) under the action of different photocatalysts

As is clear from the results in Table 1, the photoinitiated, radical tandem reaction of the present invention for the preparation of indolyltetrahydropyridinediones (compound of formula I-1) is only based on tris (2-phenylpyridine) iridium (fac-Ir (ppy)₃) Can be carried out under catalysis.

2. Effect of additive classes on the preparation of Indolo-Tetrahydropyridinediones (Compounds of formula I-1)

According to the preparation method in example 1, 0.2mmol of indole derivative having a structural formula II-1, 0.6mmol of benzoyl chloride (aroyl chlorides), and tris (2-phenylpyridine) -iridium (fac-Ir (ppy) as a catalyst face were reacted₃) 3% mmol, additive 0.3mmol, acetonitrile (CH)₃CM) was 2mL, and the results of preparing indolyltetrahydropyridinedione (compound of formula I-1) using potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylenediamine, triethylamine, and potassium acetate as additives instead of 2,6-lutidine under the same reaction conditions as in example 1 are shown in Table 2.

TABLE 2 yield of indolo-tetrahydropyridinedione (compound of formula I-1) with different additives

As can be seen from the results in Table 2, in the reaction of the present invention, 2,6-lutidine, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylenediamine, triethylamine and potassium acetate all served as additives for preparing indolopyridyl tetralone (compound of formula I-1) by photoinitiated radical tandem reaction.

3. Influence of organic solvent species on preparation of indolyltetrahydropyridone-dione (compound of formula I-1)

According to the preparation method in example 1, 0.2mmol of indole derivative having a structural formula II-1, 0.6mmol of benzoyl chloride (aroyl chlorides), and tris (2-phenylpyridine) -iridium (fac-Ir (ppy) as a catalyst face were reacted₃) 3% mmol, 0.3mmol of additive 2,6-lutidine (2,6-lutidine), and 2mL of organic solvent, and extracting the organic solvent from acetonitrile (CH)₃CM) were replaced with ethyl acetate, tetrahydrofuran, acetone, 1, 4-dioxane, toluene, dichloromethane, and N, N-dimethylformamide, respectively, and the remaining reaction conditions were the same as in example 1, and the results of preparing indolopyridyl tetradione (compound of formula I-1) are shown in table 3.

TABLE 3 yield of indolo-tetrahydropyridinedione (compound of formula I-1) in different organic solvents

As can be seen from the results in Table 3, acetonitrile (CH) was used in the reaction of the present invention₃CM), ethyl acetate, tetrahydrofuran, acetone, 1, 4-dioxane, toluene, dichloromethane and N, N-dimethylformamide can be used as organic solvents for preparing the indolyltetrahydropyridinedione (the compound with the structural formula I-1) by the photoinitiated free radical cascade reaction.

4. Effect of acid chloride addition on preparation of Indolo-tetrahydropyridinedione (Compound of formula I-1)

According to the preparation method in example 1, 0.2mmol of indole derivative having a structural formula II-1, benzoyl chloride (aroyl chlorides), tris (2-phenylpyridine) iridium (fac-Ir (ppy) as a catalyst surface were reacted₃) The results of obtaining indolylopyridinedione (compound of the formula I-1) were shown in Table 4, except that the reaction conditions were the same as in example 1 except that the amounts of 3% mmol, 0.3mmol of 2,6-lutidine as additive and 2mL of dichloromethane as organic solvent were changed from 0.2mmol to 0.4mmol, 0.6mmol, 0.8mmol and 1.0mmol, respectively.

TABLE 4 yield of indolo-tetrahydropyridinedione (compound of formula I-1) with different amounts of acid chloride added

As can be seen from the results in Table 4, the addition of acid chloride in the reaction of the present invention in a molar ratio of indole derivative to acid chloride of 1:1 to 1:5 enables the photoinitiated radical tandem reaction to prepare the indolyltetrahydropyridinedione (compound of formula I-1).

5. Effect of additive addition on preparation of Indolo-tetrahydropyridinedione (Compound of formula I-1)

According to the preparation method in example 1, 0.2mmol of indole derivative having a structural formula II-1, 0.6mmol of benzoyl chloride (aroyl chlorides), and tris (2-phenylpyridine) -iridium (fac-Ir (ppy) as a catalyst face were reacted₃) 3% mmol, additive 2, 6-dimethylpyridine, acetonitrile (CH)₃CM) was added to the reaction mixture, and 2mL of an additive, 2,6-lutidine, was added in an amount of 0.1mmol, 0.2mmol, 0.3mmol, 0.4mmol and 0.5mol, respectively, under the same reaction conditions as in example 1, to give indolyltetrahydropyridinedione (compound of formula I-1) as shown in Table 5.

TABLE 5 yield of indolo-tetrahydropyridinedione (compound of formula I-1) with different additive additions

As can be seen from the results in Table 5, the addition of the additive in the reaction of the present invention in a molar ratio of indole derivative to additive of 1:0.5 to 1:2.5 enables the photoinitiated radical tandem reaction to prepare the indolopyridyl-tetrahydropyridinedione (compound of formula I-1).

6. Influence of different illumination conditions on preparation of indolyltetrahydropyridine dione (compound with structural formula I-1)

According to the preparation method in example 1, 0.2mmol of indole derivative having a structural formula II-1, 0.6mmol of benzoyl chloride (aroyl chlorides), and tris (2-phenylpyridine) -iridium (fac-Ir (ppy) as a catalyst face were reacted₃) 3% mmol, additive 2,6-lutidine 0.2mmol, acetonitrile (CH)₃CM)2mL, and the reaction was carried out under different illumination conditions, and the other reaction conditions were the same as in example 1, and the results of preparing indolyltetrahydropyridinedione (compound of formula I-1) are shown in Table 5.

TABLE 6 yield of indolo-tetrahydropyridinedione (compound of formula I-1) under different light conditions

The results in Table 6 show that the preparation of the indolylpyridyl-tetrahydropyridine dione (compound with the structural formula I-1) through the photoinitiated radical tandem reaction can be realized under the condition that the reaction is carried out for 4-24 hours under the irradiation of blue light with the power of 9-40W.

The different conditions used in the above examples for the preparation of other indolo-tetrahydropyridinediones and their derivatives gave the same results, demonstrating freedom in photoinitiationIn the process of preparing the indolyltetrahydropyridine dione and the derivatives thereof by the base series reaction, the indole derivatives can be any one of II-1-II-6 structural formulas, the acyl chloride can be any one of III-1-III-6 structural formulas, the additive can be any one of 2, 6-dimethylpyridine, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylene Diamine (DABCO), triethylamine or potassium acetate, and the photocatalyst can be any one of the facial type tris (2-phenylpyridine) iridium (fac-Ir (ppy)₃) The organic solvent is any one of tetrahydrofuran, toluene, DMSO, acetone, ethyl acetate, acetonitrile, dichloromethane or N, N-dimethylformamide, the molar ratio of the indole derivative to the additive is 1: 0.5-2.5, the molar ratio of the indole derivative to the photocatalyst is 1: 0.5-3.0%, and the irradiation is carried out for 4-24 hours under the blue light with the power of 9-40W under the illumination condition.

Mechanism study

The reaction mechanism of the synthesis method (photocatalytic radical tandem reaction) of the ketone and sulfone containing indolopyridyl dione derivatives related to the present invention was investigated by a series of experiments in the following reaction formula:

the research finds that: under exactly the same experimental conditions as in example 1, no significant target product was detected when 3.0 equivalents of a radical scavenger (2,2,6, 6-tetramethylpiperidine oxide (TEMPO) or 2, 6-di-tert-butyl-4-methylphenol (BHT)) were added. This illustrates a process in which radicals may be involved in the reaction process of the preparation process of the present invention. The product of radical coupling was captured by High Resolution Mass Spectrometry (HRMS). In addition, the results of fluorescence quenching experiments are shown in FIG. 1 (wherein PC is a photocatalyst, PhCOCl is benzoyl chloride, PhSO₂Cl is benzenesulfonyl chloride), indicating that benzoyl chloride and benzenesulfonyl chloride can effectively quench excited state of photocatalyst fac-Ir (ppy)₃ ^*. The cyclic voltammetry experiment results indicated that the reduction potential of benzoyl chloride was-0.96V (E)_red-0.96V vs SCE in MeCN), which suggests that benzoyl chloride can be oxidatively quenched by means of one electron transferExcited state photocatalyst fac-Ir (ppy)₃ ^*(E_ox-1.73V vs SCE in MeCN). In addition, the lamp switching experiment shows that the yield of the indolopyridone derivative is obviously increased in the lamp switching period (as shown in figure 2), and the reaction of the invention is proved to be involved in the process of free radical chain growth.

Based on the above conclusions, the reaction mechanism of the present invention as shown in FIG. 3 (taking the reaction of benzoyl chloride as an example) is proposed. According to the results of the above-mentioned research experiment, the reaction mechanism was proposed for the radical tandem cyclization system, first, the ground state of [ fac-Ir (ppy)₃]fac-Ir (ppy) capable of absorbing photon energy and changing into excited state under irradiation of blue LED lamp₃ ^*]Subsequently excited state of [ fac-Ir (ppy)₃ ^*]And the radical precursor benzoyl chloride, the result of which is a Single Electron Transfer (SET) process, which results in the benzoyl chloride taking one electron and then homolytic cleavage to form a benzoyl radical and leaving a chloride ion. The photosensitizer in an excited state loses one electron and returns to a ground state, then benzoyl free radical is added to a carbon-carbon double bond of a substrate to generate a tertiary carbon free radical intermediate a, the free radical intermediate a is subjected to intramolecular free radical addition cyclization to obtain a free radical intermediate b, then the free radical intermediate b can possibly undergo chain reaction with benzoyl chloride to generate an acyl free radical and an intermediate c, on the other hand, the free radical intermediate b reacts with the photosensitizer to return the photosensitizer to an initial state and generate an intermediate c, and finally, the intermediate c removes one proton under the action of alkali to generate a target product I-1. The same reaction mechanism can be applied to the preparation of other indolyltetrahydropyridinediones and derivatives thereof by the photo-initiated radical tandem reaction.

To further demonstrate the versatility and synthetic utility of this transformation, we also tried some valuable free radical precursors as shown below. Nitrile compounds are versatile synthetic intermediates that can be converted into many high value organic compounds such as carboxylic acids, amines, or amides due to their abundant and superior activity. In view of this, we have used bromoacetonitrile and cyclobutyloxime ester as cyano sources instead of acid chlorides under standard reaction conditions to give indolopyridyl-tetrahydropyridinediones with alkylnitriles in good yields. In addition, the fluorine-containing group is considered to be a unique structure closely related to the physicochemical properties of drug molecules, and thus plays an important role in drug design and development. To this end, we tried to introduce trifluoromethyl and perfluoroalkyl groups into the indolyltetrahydropyridinedione backbone with trifluoromethanesulfonyl chloride and perfluoroalkyl iodide as radical precursors for the corresponding fluoro groups as shown in examples 49-52 below.

Example 49

A compound (3- (2,4,5-trimethyl-1,3-dioxo-2,3,4,5-tetrahydro-1H-pyrido [4,3-b ] indol-4-yl) propanatrile) having a structural formula I-48 was prepared by the following method:

r in example 1³Is composed of

Replacement of acid chloride of (A) by R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 53.1mg of the compound of the formula I-48 (white solid, yield 90%).

¹H NMR(600MHz,Chloroform-d)δ8.32(d,J＝7.7Hz,1H),7.44–7.35(m,3H),3.95(s,3H),3.39(s, 3H),2.88–2.82(m,1H),2.49(m,1H),2.13(m,1H),1.94(m,1H),1.83(s,3H)。¹³C NMR(151MHz, Chloroform-d)δ174.9,161.6,143.8,138.9,124.4,124.3,123.2,121.5,117.7,109.6,105.0,46.4,34.6,32.3, 26.7,25.8,13.7。HRMS(ESI)calcd.for C₁₇H₁₇N₃O₂[M+Na]⁺:318.1213,found 318.1220。

Example 50

A compound (5- (2,4,5-trimethyl-1,3-dioxo-2,3,4,5-tetrahydro-1H-pyrido [4,3-b ] indole-4-yl) pentanantride) having a structural formula I-49 was prepared as follows:

r in example 1³Is composed of

Replacement of acid chloride of (A) by R³Is composed of

The reaction was carried out in the same manner as in example 1 to give 53.6mg of a compound of the formula I-49 (white solid, yield 83%).

¹H NMR(600MHz,Chloroform-d)δ8.33(d,J＝7.3Hz,1H),7.42–7.35(m,3H),3.94(s,3H),3.40(s, 3H),2.48(m,1H),2.26–2.17(m,3H),1.78(s,3H),1.64–1.59(m,1H),1.54(m,1H),1.14–1.08(m,1H),1.03 –0.97(m,1H)。¹³C NMR(151MHz,Chloroform-d)δ176.1,162.0,146.1,138.7,124.4,123.9,122.9,121.5, 119.0,109.4,104.5,47.1,38.5,32.1,26.6,26.1,25.1,24.7,16.7。HRMS(ESI)calcd.for C₁₉H₂₁N₃O₂[M+Na]⁺: 346.1526,found 346.1530。

Example 51

A compound (2,4, 5-trimethy-4- (2,2,2-trifluoroethyl) -4, 5-dihydo-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) with a structural formula I-50 is prepared by the following method:

r in example 1³Is composed of

Replacement of acid chloride of (A) by R³is-CF₃The reaction was carried out in the same manner as in example 1 to obtain 31.8mg of a compound of the formula I-50 (white solid, yield 49%).

¹H NMR(600MHz,Chloroform-d)δ8.35(d,J＝7.6Hz,1H),7.42–7.36(m,3H),3.93(s,3H),3.59– 3.54(m,1H),3.42(s,3H),3.05–2.99(m,1H),1.79(s,3H)。¹³C NMR(151MHz,Chloroform-d)δ174.4, 161.5,143.3,138.8,124.8(m),124.4,124.1,123.0,122.0,121.7,109.4,104.2,42.7(m),42.0(m),32.0,27.0, 26.8。HRMS(ESI)calcd.for C₁₆H₁₅F₃N₂O₂[M+Na]⁺:347.0978,found 347.0995。

Example 52

A compound of formula I-51 (4- (2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11, 11-hexanicosafluoroundecyl) -2,4, 5-trimethy-4, 5-dihydro-1H-pyrido [4,3-b ] indole-1,3(2H) -dione) is prepared as follows:

r in example 1³Is composed of

Replacement of acid chloride of (A) by R³is-C₁₀F₂₁The reaction was carried out in the same manner as in example 1 to give 126.9mg of the compound of the formula I-51 (white solid, yield 82%).

¹H NMR(600MHz,Chloroform-d)δ8.36(d,J＝7.5Hz,1H),7.44–7.36(m,3H),3.93(s,3H),3.64(dd, J＝36.3,15.7Hz,1H),3.42(s,3H),2.97(m,1H),1.82(s,3H)。¹³C NMR(151MHz,Chloroform-d)δ174.4, 161.6,143.5,138.7,124.5,124.1,123.0,121.7,109.3,104.0,42.1,38.4,38.3,32.0,27.6,26.8。HRMS(ESI) calcd.for C₂₅H₁₅F21N₂O₂[M+H]⁺:775.0871,found 775.0869。

In summary, the invention discloses a method for preparing indolyltetrahydropyridinedione and derivatives thereof by photoinitiated free radical series reaction, which mainly comprises the step of reacting indole derivatives with acyl chloride or sulfonyl chloride in the presence of a facial form of tris (2-phenylpyridine) iridium (fac-Ir (ppy)₃) The indole tetrahydropyridine dione and the derivative thereof are obtained by carrying out a light irradiation reaction under the catalysis of the catalyst, and the indole tetrahydropyridine dione and the derivative thereof belong to the generation of a plurality of indole tetrahydropyridine dione derivatives containing ketone and sulfone through a series cyclization reaction catalyzed by light oxidation reduction between a Michael acceptor and a free radical (wherein the free radical is derived from acyl chloride or sulfonyl chloride). In the preparation method of the photo-initiation free radical series reaction, the source of free radicals is wide (derived from easily available acyl chloride or sulfonyl chloride), the free radical series strategy provides a simple solution for the simple synthesis of various indolo-tetrahydropyridinedione derivatives, and further application of the preparation method can create more synthesis values in the foreseeable future.

Finally, the above embodiments are only intended to illustrate the technical solutions of the present invention and not to limit the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions, and all of them should be covered by the claims of the present invention.

Claims (9)

1. A method for preparing indolopyridyl tetrahdione and derivatives thereof by photoinitiated free radical series reaction is characterized in that the reaction formula of the method is as follows:

wherein R is¹is-CH₃or-CH₂C₆H₅A group;

R²is-CH₃、

Any one of the groups;

R³is composed of

-CF₃or-C₁₀F₂₁Any one of the groups;

the additive is any one of 2, 6-dimethyl pyridine, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylene Diamine (DABCO), triethylamine or potassium acetate;

the photocatalyst is a planar tris (2-phenylpyridine) iridium (fac-Ir (ppy)₃)。

2. The method according to claim 1, characterized in that it is specifically as follows: adding a photocatalyst and an additive into an indole derivative II and an acyl chloride organic solvent, irradiating by blue light under the argon atmosphere (argon balloon) for reaction, concentrating and purifying to obtain the indolylpentahydropyridinedione and the derivative thereof.

3. The method according to claim 2, wherein the molar ratio of the indole derivative to the acid chloride is 1: 1-5.

4. The method according to claim 2, wherein the organic solvent is any one of tetrahydrofuran, toluene, DMSO, acetone, ethyl acetate, acetonitrile, dichloromethane, or N, N-dimethylformamide.

5. The method according to claim 2, wherein the molar ratio of the indole derivative to the additive is 1: 0.5-2.5; the mol ratio of the indole derivative to the photocatalyst is 1: 0.5-3.0%.

6. The method according to claim 2, characterized in that said blue light irradiation is in particular: irradiating for 4-24 h under the blue light with the power of 9-40W.

7. The method of claim 2, wherein the purification is: and purifying the concentrated solid by using a column chromatography method, wherein a mixed solvent formed by petroleum ether and ethyl acetate in a volume ratio of 5: 1-1: 2 is used as an eluent in the purification process.

8. Indolo-tetrahydropyridinedione and derivatives thereof prepared by the preparation method according to any one of claims 1 to 7.

9. The indolopyridone-tetrahydropyridine dione and derivatives thereof according to claim 8, wherein the structure of the indolopyridone-tetrahydropyridine dione and derivatives thereof is as follows I-1 to I-51:

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